scholarly journals Predicting Diagnostic Potential of Cathepsin in Epithelial Ovarian Cancer: A Design Validated by Computational, Biophysical and Electrochemical Data

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 53
Author(s):  
Hemangi Ranade ◽  
Priya Paliwal ◽  
Anis Ahmad Chaudhary ◽  
Sakshi Piplani ◽  
Hassan Ahmed Rudayni ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protease Inhibitor ◽  
Epithelial Ovarian Cancer ◽  
Cystatin C ◽  
Gynecological Cancer ◽  
Cathepsin L ◽  
Cathepsin K ◽  
Binding Energies ◽  
Cysteine Protease Inhibitor ◽  
Diagnostic Potential

Background: Epithelial ovarian cancer remains one of the leading variants of gynecological cancer with a high mortality rate. Feasibility and technical competence for screening and detection of epithelial ovarian cancer remain a major obstacle and the development of point of care diagnostics (POCD) may offer a simple solution for monitoring its progression. Cathepsins have been implicated as biomarkers for cancer progression and metastasis; being a protease, it has an inherent tendency to interact with Cystatin C, a cysteine protease inhibitor. This interaction was assessed for designing a POCD module. Methods: A combinatorial approach encompassing computational, biophysical and electron-transfer kinetics has been used to assess this protease-inhibitor interaction. Results: Calculations predicted two cathepsin candidates, Cathepsin K and Cathepsin L based on their binding energies and structural alignment and both predictions were confirmed experimentally. Differential pulse voltammetry was used to verify the potency of Cathepsin K and Cathepsin L interaction with Cystatin C and assess the selectivity and sensitivity of their electrochemical interactions. Electrochemical measurements indicated selectivity for both the ligands, but with increasing concentrations, there was a marked difference in the sensitivity of the detection. Conclusions: This work validated the utility of dry-lab integration in the wet-lab technique to generate leads for the design of electrochemical diagnostics for epithelial ovarian cancer.

scholarly journals Presence of Anti-cystatin C–positive Dendritic Cells or Macrophages and Localization of Cysteine Proteases in the Apical Bud of the Enamel Organ in the Rat Incisor

2005 ◽  
Vol 53 (5) ◽  
pp. 643-651 ◽  
Author(s):  
Sumio Nishikawa
Keyword(s):  
Dendritic Cells ◽  
Cystatin C ◽  
Cysteine Protease ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Cysteine Protease Inhibitor ◽  
Enamel Organ ◽  
Apical Bud ◽  
Apical Buds ◽  
Proliferation And Differentiation

Cystatin C, a cysteine protease inhibitor, was examined in the apical buds of rat incisors by immunohistochemistry, because in transition and maturation zones most of the dendritic cells in the papillary layer are anti-cystatin C–positive. Anti-cystatin C–labeled cells were sparse and localized to the proliferation and differentiation zones, constituting the apical bud of 5-week-old rat incisors. These cells were considered macrophages or dendritic cells, based on their reactivity with OX6 and ED1, as well as their ultrastructure. Basement membrane at the periphery of apical bud was also labeled by anti-cystatin C antibody. The apical buds included a few apoptotic fragments and weak reactivity with antibody to cathepsin L, a cysteine protease. Reactivity to anti-cystatin C and anti-cathepsin ∗∗∗L antibodies was also detected in the apical bud of newborn rat incisors. These results suggest that the cystatin C–positive macrophages or dendritic cells are involved in normal incisor formation. They may be related to the clearance of apoptotic cells or protection from putative cysteine protease activity.

scholarly journals Overexpression of Cathepsin L is associated with chemoresistance and invasion of epithelial ovarian cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (29) ◽  
pp. 45995-46001 ◽  
Author(s):  
Hongying Sui ◽  
Caixia Shi ◽  
Zhipeng Yan ◽  
Mei Wu
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cathepsin L

scholarly journals Evaluation of Diagnostic Potential of Epigenetically Deregulated MiRNAs in Epithelial Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Vivek Kumar ◽  
Sameer Gupta ◽  
Amrita Chaurasia ◽  
Manisha Sachan
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Progression ◽  
Early Stage ◽  
Ovarian Tissue ◽  
Characteristic Curve ◽  
Mirna Gene ◽  
Serum Samples ◽  
Cancer Management ◽  
Diagnostic Potential

BackgroundEpithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies among women worldwide. Early diagnosis of EOC could help in ovarian cancer management. MicroRNAs, a class of small non-coding RNA molecules, are known to be involved in post-transcriptional regulation of ~60% of human genes. Aberrantly expressed miRNAs associated with disease progression are confined in lipid or lipoprotein and secreted as extracellular miRNA in body fluid such as plasma, serum, and urine. MiRNAs are stably present in the circulation and recently have gained an importance to serve as a minimally invasive biomarker for early detection of epithelial ovarian cancer.MethodsGenome-wide methylation pattern of six EOC and two normal ovarian tissue samples revealed differential methylation regions of miRNA gene promoter through MeDIP-NGS sequencing. Based on log2FC and p-value, three hypomethylated miRNAs (miR-205, miR-200c, and miR-141) known to have a potential role in ovarian cancer progression were selected for expression analysis through qRT-PCR. The expression of selected miRNAs was analyzed in 115 tissue (85 EOC, 30 normal) and 65 matched serum (51 EOC and 14 normal) samples.ResultsAll three miRNAs (miR-205, miR-200c, and miR-141) showed significantly higher expression in both tissue and serum cohorts when compared with normal controls (p < 0.0001). The receiver operating characteristic curve analysis of miR-205, miR-200c, and miR-141 has area under the curve (AUC) values of 87.6 (p < 0.0001), 78.2 (p < 0.0001), and 86.0 (p < 0.0001), respectively; in advance-stage serum samples, however, ROC has AUC values of 88.1 (p < 0.0001), 78.9 (p < 0.0001), and 86.7 (p < 0.0001), respectively, in early-stage serum samples. The combined diagnostic potential of the three miRNAs in advance-stage serum samples and early-stage serum samples has AUC values of 95.9 (95% CI: 0.925–1.012; sensitivity = 96.6% and specificity = 80.0%) and 98.1 (95% CI: 0.941–1.021; sensitivity = 90.5% and specificity = 100%), respectively.ConclusionOur data correlate the epigenetic deregulation of the miRNA genes with their expression. In addition, the miRNA panel (miR-205 + miR-200c + miR-141) has a much higher AUC, sensitivity, and specificity to predict EOC at an early stage in both tissue and serum samples.

scholarly journals Kinetics of HE4 and CA125 as prognosis biomarkers during neoadjuvant chemotherapy in advanced epithelial ovarian cancer

2021 ◽  
Author(s):  
Jorge A. Alegría-Baños ◽  
José C. Jiménez-López ◽  
Arely Vergara-Castañeda ◽  
David F. Cantú de León ◽  
Alejandro Mohar-Betancourt ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Epithelial Ovarian Cancer ◽  
Gynecological Cancer ◽  
Response To Treatment ◽  
Serum Samples ◽  
Prospective Longitudinal Study ◽  
Advanced Stages ◽  
Advanced Epithelial Ovarian Cancer ◽  
Prospective Longitudinal

Abstract Background Ovarian cancer (OC) is considered the most lethal gynecological cancer, of which more than 65% cases are diagnosed in advanced stages, requiring platinum-based neoadjuvant chemotherapy (NACT). Methods A prospective-longitudinal study was conducted among women with advanced epithelial ovarian cancer (AEOC), III and IV stages, and treated with NACT, at the National Cancer Institute – Mexico, from July 2017 to July 2018. Serum samples were obtained for quantification of CA125 and HE4 using ELISA at the first and in each of the three NACT cycles. The therapeutic response was evaluated through standard tomography. We determined whether CA125 and HE4, alone or in combination, were associated with TR to NACT during follow up. Results 53 patients aged 38 to 79 years were included, 92.4% presented papillary serous subtype OC. Higher serum HE4 levels were observed in patients with non-tomographic response (6.89 vs 5.19 pmol/mL; p = 0.031), specially during the second (p = 0.039) and third cycle of NACT (p = 0.031). Multivariate-adjusted models showed an association between HE4 levels and TR, from the second treatment cycle (p = 0.042) to the third cycle (p = 0.033). Changes from baseline HE4 levels during the first cycle was negative associated with TR. No associations were found between CA125 and TR. Conclusions Serum HE4 levels were independently associated with TR among patients with AOEC treated with NACT, also a reduction between baseline HE4 and first chemotherapy levels was also independently associated with the TR. These findings might be relevant for predicting a lack of response to treatment.

scholarly journals A Swedish Nationwide prospective study of oncological and reproductive outcome following fertility-sparing surgery for treatment of early stage epithelial ovarian cancer in young women

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Gry Johansen ◽  
Pernilla Dahm-Kähler ◽  
Christian Staf ◽  
Angelique Flöter Rådestad ◽  
Kenny A. Rodriguez-Wallberg
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Young Women ◽  
Gynecological Cancer ◽  
Population Based ◽  
Prognostic Impact ◽  
Fertility Sparing Surgery ◽  
Quality Register ◽  
Fertility Sparing ◽  
Histologic Subtypes

Abstract Background Epithelial ovarian cancer (EOC) is rare in women of reproductive age and fertility-sparing surgery (FSS) may be applied in early stages. The purpose of this study was to investigate the safety and efficacy of FSS for treatment of EOC. Methods The Swedish nationwide population-based Quality Register for Gynecological Cancer was used to identify all women 18–40 years of age diagnosed with stage I EOC between 2008 and 2015. Detailed data on surgery, staging, histopathology, and follow-up were extracted and reviewed. Cross-linking of individuals to population-based registries allowed retrieval of data on obstetrical and reproductive outcomes after FSS. Disease-free survival (DFS) and overall survival (OS) rates were compared (Kaplan-Meier method) between women who underwent FSS vs. radical surgery (RS). Results In total 83 women were identified; 36 who had FSS performed and 47 RS. The 5-year OS rate was 92% and no statistical differences between DFS or OS were found between women treated by FSS or RS. The recurrence rate after RS was 13% compared to 6% after FSS. Recurrences were more frequently found in women with stage IC tumor or with histologic subtypes with more aggressive behavior. In the FSS cohort, nine women gave birth to 12 healthy children, all delivered at fullterm. Only one women had received assisted reproductive technology treatment. Conclusion In this nationwide population-based cohort study natural fertility was maintained after FSS. Specific histologic subtypes showed greater prognostic impact on the oncological outcome than the use of FSS. Recurrences occurred after FSS, but none in the uterus, which questions the need of hysterectomy in young women with EOC. Trial registration This article reports the results of a healthcare intervention using the data prospectively registered in the Swedish population-based registries including the Quality Register for Gynecological Cancer, the National Death Register, the Swedish Medical Birth Register, and the National Quality Register for Assisted Reproduction.

A cysteine protease inhibitor blocks SARS-CoV-2 infection of human and monkey cells

2020 ◽  
Author(s):  
Drake M. Mellott ◽  
Chien-Te Tseng ◽  
Aleksandra Drelich ◽  
Pavla Fajtová ◽  
Bala C. Chenna ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Host Cell ◽  
Cysteine Protease ◽  
Cleavage Site ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Protein Processing ◽  
Spike Protein ◽  
Cysteine Protease Inhibitor ◽  
Viral Infectivity

ABSTRACTK777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ACE2, Caco-2, A549/ACE2, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ACE2, and 4 nM for HeLa/ACE2 cells. In contrast, Calu-3 and Caco-2 cells had EC50 values in the low micromolar range. No toxicity of K777 was observed for any of the host cells at 10-100 μM inhibitor. K777 did not inhibit activity of the papain-like cysteine protease and 3CL cysteine protease, encoded by SARS-CoV-2 at concentrations of ≤ 100 μM. These results suggested that K777 exerts its potent anti-viral activity by inactivation of mammalian cysteine proteases which are essential to viral infectivity. Using a propargyl derivative of K777 as an activity-based probe, K777 selectively targeted cathepsin B and cathepsin L in Vero E6 cells. However only cathepsin L cleaved the SARS-CoV-2 spike protein and K777 blocked this proteolysis. The site of spike protein cleavage by cathepsin L was in the S1 domain of SARS-CoV-2, differing from the cleavage site observed in the SARS CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of viral spike protein processing.SIGNIFICANCEThe virus causing COVID-19 is highly infectious and has resulted in a global pandemic. We confirm that a cysteine protease inhibitor, approved by the FDA as a clinical-stage compound, inhibits SARS-CoV-2 infection of several human and monkey cell lines with notable(nanomolar) efficacy. The mechanism of action of this inhibitor is identified as a specific inhibition of host cell cathepsin L. This in turn inhibits host cell processing of the coronaviral spike protein, a step required for cell entry. Neither of the coronaviral proteases are inhibited, and the cleavage site of spike protein processing is different from that reported in other coronaviruses. Hypotheses to explain the differential activity of the inhibitor with different cell types are discussed.

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