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Search results for: KLK5

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#32728162   2020/07/29 To Up

Altered mechanisms of genital development identified through integration of DNA methylation and genomic measures in hypospadias.

Hypospadias is a common birth defect where the urethral opening forms on the ventral side of the penis. We performed integrative methylomic, genomic, and transcriptomic analyses to characterize sites of DNA methylation that influence genital development. In case-control and case-only epigenome-wide association studies (EWAS) of preputial tissue we identified 25 CpGs associated with hypospadias characteristics and used one-sample two stage least squares Mendelian randomization (2SLS MR) to show a causal relationship for 21 of the CpGs. The largest difference was 15.7% lower beta-value at cg14436889 among hypospadias cases than controls (EWAS P = 5.4e-7) and is likely causal (2SLS MR P = 9.8e-15). Integrative annotation using two-sample Mendelian randomization of these methylation regions highlight potentially causal roles of genes involved in germ layer differentiation (WDHD1, DNM1L, TULP3), beta-catenin signaling (PKP2, UBE2R2, TNKS), androgens (CYP4A11, CYP4A22, CYP4B1, CYP4X1, CYP4Z2P, EPHX1, CD33/SIGLEC3, SIGLEC5, SIGLEC7, KLK5, KLK7, KLK10, KLK13, KLK14), and reproductive traits (ACAA1, PLCD1, EFCAB4B, GMCL1, MKRN2, DNM1L, TEAD4, TSPAN9, KLK family). This study identified CpGs that remained differentially methylated after urogenital development and used the most relevant tissue sample available to study hypospadias. We identified multiple methylation sites and candidate genes that can be further evaluated for their roles in regulating urogenital development.
Melissa A Richard, Pagna Sok, Stephen Canon, Wendy N Nembhard, Austin L Brown, Erin C Peckham-Gregory, Minh Ton, Erik A Ehli, Noah A Kallsen, Shanna A Peyton, Gareth E Davies, Ashay Patel, Ismael Zamilpa, Charlotte A Hobbs, Michael E Scheurer, Philip J Lupo

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#32461336   // To Up

Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven, inflammatory disease of the esophagus and is associated with impaired barrier function. Evidence is emerging that loss of esophageal expression of the serine peptidase inhibitor, kazal type 7 (SPINK7), is an upstream event in EoE pathogenesis. Here, we provide evidence that loss of mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Overexpression of in differentiated esophageal epithelial cells recapitulated the effect of gene silencing, including barrier impairment and loss of desmoglein-1 expression. Conversely, KLK5 deficiency attenuated allergen-induced esophageal protease activity, modified commensal microbiome composition, and attenuated eosinophilia in a murine model of EoE. Inhibition of PAR2 blunted the cytokine production associated with loss of in epithelial cells and attenuated the allergen-induced esophageal eosinophilia in vivo. Clinical samples substantiated dysregulated PAR2 expression in the esophagus of patients with EoE, and delivery of the clinically approved drug α1 antitrypsin (A1AT, a protease inhibitor) inhibited experimental EoE. These findings demonstrate a role for the balance between KLK5 and protease inhibitors in the esophagus and highlight EoE as a protease-mediated disease. We suggest that antagonizing KLK5 and/or PAR2 has potential to be therapeutic for EoE.
Nurit P Azouz, Andrea M Klingler, Purnima Pathre, John A Besse, Netali Ben Baruch-Morgenstern, Adina Y Ballaban, Garrett A Osswald, Michael Brusilovsky, Jeff E Habel, Julie M Caldwell, Mario A Ynga-Durand, Pablo J Abonia, Yueh-Chiang Hu, Ting Wen, Marc E Rothenberg

2076 related Products with: Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis.

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#32442469   2020/05/19 To Up

Cathelicidin represents a new target for manipulation of skin inflammation in Netherton syndrome.

Netherton syndrome (NS) is a severe ichthyosis caused by inactivating mutations in the SPINK5 gene encoding the serine protease inhibitor LEKTI. Spink5 mice recapitulate NS and die perinatally from extensive dehydration as a result of a severe defect of the epidermal barrier. We showed that deletion of Klk5 in Spink5 rescues neonatal lethality (Furio et al., 2015). However, Spink5Klk5 mice developed skin shedding and inflammation during the first week from birth and the majority (70%) succumbed on P7. The remaining mice lived short (i.e. mean survival was 5 months) indicating alternative inflammatory pathways. Since cathelicidin is increased in Spink5 epidermis, we investigated whether it could be implicated in NS pathology. Ablation of Camp in Spink5 suppressed epidermal inflammation and restored abnormal epidermal differentiation, nevertheless, it failed to inhibit overdesquamation and Spink5Camp succumbed perinatally due to skin barrier defect, similarly to Spink5. Joint invalidation of Klk5 and Camp significantly extended survival of Spink5Klk5Camp mice. We provide evidence that cathelicidin is implicated in NS-associated skin inflammation in vivo. Therefore, marketed products that are known to reduce cathelicidin expression could be repurposed for the management of NS.
Eleni Zingkou, Georgios Pampalakis, Georgia Sotiropoulou

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#32366393   // To Up

Gene Expression of Kallikreins in Breast Cancer Cell Lines.

This study analyzed the gene expression of the "classic" KLK1 and "new" kallikreins KLK4-KLK15, in relation to the molecular characteristics and in vitro invasiveness of 21 breast cancer (BC) and three normal breast-derived cell lines (CLs).
Rafał Watrowski, Dan Cacsire Castillo-Tong, Eva Obermayr, Robert Zeillinger

1662 related Products with: Gene Expression of Kallikreins in Breast Cancer Cell Lines.

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#32086131   2020/02/18 To Up

Decreased shedding dipeptidyl peptidase 4 from membrane in Hashimoto's thyroiditis.

This study aimed to determine the concentration and enzymatic activity of dipeptidyl peptidase 4 (DPP4) in serum and peripheral blood mononuclear cells (PBMCs) from patients with Hashimoto's thyroiditis (HT) and to explore the potential mechanism of the abnormal DPP4 in HT development.
Wenjie Xu, Yongping Liu, Xuebing Cheng, Na Huang, Ningning Hou, Hongsheng Wang, Fang Han, Xue Han, Xiaodong Sun

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#32056846   2020/01/07 To Up

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses.

Viruses possessing class I fusion proteins require proteolytic activation by host cell proteases to mediate fusion with the host cell membrane. The mammalian SPINT2 gene encodes a protease inhibitor that targets trypsin-like serine proteases. Here we show the protease inhibitor, SPINT2, restricts cleavage-activation efficiently for a range of influenza viruses and for human metapneumovirus (HMPV). SPINT2 treatment resulted in the cleavage and fusion inhibition of full-length influenza A/CA/04/09 (H1N1) HA, A/Aichi/68 (H3N2) HA, A/Shanghai/2/2013 (H7N9) HA and HMPV F when activated by trypsin, recombinant matriptase or KLK5. We also demonstrate that SPINT2 was able to reduce viral growth of influenza A/CA/04/09 H1N1 and A/X31 H3N2 in cell culture by inhibiting matriptase or TMPRSS2. Moreover, inhibition efficacy did not differ whether SPINT2 was added at the time of infection or 24 h post-infection. Our data suggest that the SPINT2 inhibitor has a strong potential to serve as a novel broad-spectrum antiviral.
Marco R Straus, Jonathan T Kinder, Michal Segall, Rebecca Ellis Dutch, Gary R Whittaker

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#31955796   2019/12/30 To Up

Kallikrein-related Peptidase 5 (KLK5) Expression and Distribution in Canine Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common types of malignant skin cancer in dogs, representing 3.9-10.4% of all canine skin tumours. Although the metastatic potential of cSCC is debated, it appears to mimic that observed in man. In man, predictive histopathological features for metastasis include tumour depth, lesions >5-6 mm in depth, and invasion of muscle, cartilage or bone. In dogs, some reports have focused on the clinical features and long-term progression of cSCC, but a gold standard treatment has not yet been developed. We explored the protein expression of kallikrein-related peptidase 5 (KLK5), an important modulator of skin homeostasis, in normal canine skin and in examples of cSCC. KLK5 was highly expressed in the upper stratum granulosum, stratum corneum, hair follicles and sweat glands, skin sites where human KLK5 has been shown to be involved in physiological processes including keratinocyte desquamation, antimicrobial defence, lipid permeability and pigmentation. In cSCC, tumour cells at the deep margin, as well as those in the centre of keratin pearls, displayed cytoplasmic expression of KLK5. Some of the KLK5 immunoreactive cells also expressed vimentin, suggesting that they may be undergoing epithelial-mesenchymal transition and therefore have a more invasive behaviour than those expressing only KLK5. KLK5 may be a novel molecular biomarker useful for predicting prognosis of cSSC in dogs.
A Ortloff, F A Bustamante, L Molina, J Ojeda, C D Figueroa, P Ehrenfeld

2724 related Products with: Kallikrein-related Peptidase 5 (KLK5) Expression and Distribution in Canine Cutaneous Squamous Cell Carcinoma.

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#31572680   2019/09/11 To Up

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line.

The oral multi-targeted tyrosine kinase inhibitor (TKI) anlotinib is effective for non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, a fraction of patients remains non-responsive, raising the need of how to identify anlotinib-responsive patients. In the present study, we aimed to screen potential biomarkers for anlotinib-responsive stratification via integrated transcriptome analysis. Comparing with the anlotinib-sensitive lung cancer cell NCI-H1975, we found 1,315 genes were differentially expressed in anlotinib-resistant NCI-H1975 cells. Among the enriched angiogenesis-related genes, we observed high expression of and was mostly associated with poor clinical outcomes in NSCLC patients through Kaplan-Meier survival analysis in a TCGA cohort. Moreover, an independent validation in a cohort of ALTER0303 (NCT02388919) indicated that high serum levels of KLK5 and L1CAM were also associated with poor anlotinib response in NSCLC patients at 3rd line. Lastly, we demonstrated that knockdown of and increases anlotinib-induced cytotoxicity in anlotinib-resistant NCI-H1975 cells. Collectively, our study suggested serum levels of KLK5 and L1CAM potentially serve as biomarkers for anlotinib-responsive stratification in NSCLC patients at 3rd line.
Jun Lu, Qin Shi, Lele Zhang, Jun Wu, Yuqing Lou, Jie Qian, Bo Zhang, Shuyuan Wang, Huimin Wang, Xiaodong Zhao, Baohui Han

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#31550598   2019/09/12 To Up

Immunohistochemical staining of skin-expressed proteins to identify exfoliated epidermal cells for forensic purposes.

The determination of cell type in biological casework samples would be helpful to identify the type of body fluids and interpret the DNA source in forensic laboratories. Exfoliated epidermal cells are considered to be a reasonable source of touch DNA; therefore, we developed and assessed an immunohistochemistry (IHC) procedure for identifying exfoliated epidermal cells as a screening test of touch DNA samples. Among five candidate protein markers investigated in this study, keratin 10 and kallikrein-related peptidase 5 were strongly expressed in the stratum corneum layer of the skin; however, their specificity was insufficient to identify epidermal cells. In contrast, IHC for corneodesmosin (CDSN), desmocollin 1 (DSC1), and filaggrin (FLG) was considered to be applicable because of their detectability and specificity on skin swab samples. Actually, CDSN and DSC1 could be good markers for exfoliated epidermal cells on touched contact traces that were contaminated with many unidentified impurities. Besides, positivity for FLG on mock casework samples appeared to be lower than for the other markers, which might be caused by its instability. Finally, the relationship between positivity for IHC and DNA yield was analyzed using skin swab samples. Although it was difficult to determine these correlations quantitatively because of the heterogeneous distribution of cells and the presence of cell-free DNA, the DNA-quantifiable samples analyzed in this study contained at least some of IHC-positive epidermal cells. In conclusion, IHC detection of skin-enriched proteins, especially CDSN and DSC1, could be useful for screening samples that have been handled or touched by someone before DNA analysis.
Tomoko Akutsu, Hiroshi Ikegaya, Ken Watanabe, Sachio Miyasaka

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