Dickkopf-1 Levels Research Articles

Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site.

Host-related factors highly regulate the increased circulation of neutrophils during Leishmania infection. Platelet-derived Dickkopf-1 (DKK1) is established as a high-affinity ligand to LRP6. Recently, we demonstrated that DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to the draining lymph node and Th2 differentiation during Leishmania infection, suggesting the potential involvement of the DKK1-LRP6 signalling pathway in neutrophil migration in infectious diseases. In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6NKO) or BALB/c mice deficient in both PMN LRP6 and platelet DKK1 (LRP6NKO DKK1PKO). Relative to the infected wild-type BALB/c mice, reduced neutrophil activation at the infection site of LRP6NKO or LRP6NKO DKK1PKO mice was noted. The neutrophils obtained from either infected LRP6NKO or LRP6NKO DKK1PKO mice additionally showed a high level of apoptosis. Notably, the level of LRP6 expressing neutrophils was elevated in infected BALB/c mice. Relative to infected BALB/c mice, a significant reduction in parasite load was observed in both LRP6NKO and LRP6NKO DKK1PKO infected mice. Notably, DKK1 levels were comparable in the LRP6NKO and BALB/c mice in response to infection, indicating that PMN activation is the major pathway for DKK1 in promoting parasitemia. Parasite-specific components also play a crucial role in modulating neutrophil circulation in Leishmania disease. Thus, we further determine the contribution of Leishmania membrane components in the migration of neutrophils to the infection site using null mutants deficient in LPG synthesis (Δlpg1- ) or lacking all ether phospholipids (plasmalogens, LPG, and GIPLs) synthesis (Δads1- ). Relative to the WT controls, Δads1- parasite-infected mice showed a sustained decrease in neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while neutrophils returned to normal in Δlpg1- parasite-infected mice after day 3 PI. Our results suggest that DKK1 signalling and Leishmania pathogen-associated molecular patterns appear to regulate the migration and sustenance of viable activated neutrophils in the infection site resulting in chronic type 2 cell-mediated inflammation.

Associations of serum Dickkopf-1 levels with disease severity and 90-day Prognosis after spontaneous intracerebral hemorrhage: results from the prospective cohort study.

Dickkopf-1 (DKK-1) may be involved in inflammatory response and secondary brain injury after acute brain injury. We gauged serum DKK-1 levels and further assessed its correlation with disease severity and investigated its predictive value for 90-day prognosis in patients with spontaneous intracerebral hemorrhage (sICH). Serum DKK-1 levels were measured in 128 sICH patients and 128 healthy controls. The severity of sICH was assessed using the Glasgow Coma Scale (GCS) scores and hematoma volumes. Poor prognosis was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at 90days after stroke. Multivariate analysis was performed to identify associations of serum DKK-1 levels with disease severity, early neurological deterioration (END) and poor prognosis. Receiver operating characteristic curve (ROC) was built to investigate the prognostic predictive capability. The serum DKK-1 levels of patients were significantly higher than those of controls (median, 4.74ng/mL versus 1.98ng/mL; P < 0.001), and were independently correlated with hematoma volumes (ρ = 0.567, P < 0.001; t = 3.444, P = 0.001) and GCS score (ρ = -0.612, P < 0.001; t = -2.048, P = 0.043). Serum DKK-1 significantly differentiated patients at risk of END (area under ROC curve (AUC), 0.850; 95% confidence interval (CI), 0.777-0.907; P < 0.001) and poor prognosis (AUC, 0.830; 95% CI, 0.753-0.890; P < 0.001), which had similar prognostic ability, as compared to GCS scores and hematoma volumes. Subsequent Logistic regression model affirmed that GCS score, hematoma volume, and serum DKK-1 levels were independently associated with END and poor prognosis at 90days after sICH. The models, which contained them, performed well using ROC curve analysis and calibration curve analysis. Serum DKK-1 levels are markedly associated with disease severity, END and 90-day poor prognosis in sICH. Hence, serum DKK-1 is presumed to be used as a potential prognostic biomarker of sICH.

Correlation of Circulating Dickkopf-1 Level with Sonographic Findings and Radiographic Grading in Primary Knee Osteoarthritis

Correlation of Circulating Dickkopf-1 Level with Sonographic Findings and Radiographic Grading in Primary Knee Osteoarthritis

The Role of Serum Dickkopf1 and CKAP4 Levels in Diagnosing Colorectal Cancer and Measuring the Disease Severity: A Prospective Study.

Background and Objective: Colorectal cancer (CRC) is among the most common types of cancer. Although the disease is treatable in its early stages, five-year survival falls below 20% in the later stages. CEA and CA19-9 are tumor markers used in the diagnosis and follow-up of the disease in clinical practice; however, their diagnostic effectiveness is insufficient. Therefore, the identification of biomarkers that can be easily studied from serum and can diagnose CRC and determine its severity is highly important. In this context, dickkopf1 (DKK1) and cytoskeleton-associated protein 4 (CKAP4) are both promising biomarkers. Materials and Methods: Serum DKK1 and CKAP4 levels were measured in 55 patients with CRC and 40 healthy controls. The patients with CRC were divided into groups based on pathological stages and histological differentiation. The serum levels of both proteins in patients with CRC were measured preoperatively and 10 and 30 days postoperatively. Results: Serum DKK1 and CKAP4 were significantly higher in the CRC group than in the healthy controls (p < 0.05). Serum levels of both proteins rose in line with the disease stage and grade but decreased following surgical resection. A positive correlation was observed between tumor diameter and protein blood levels. The diagnostic efficacy of DKK1 and CKAP4 in CRC (approximately 95%) was higher than that of markers such as CEA and CA19-9. Conclusions: The DKK1 and CKAP4 serum values of patients with CRC are promising biomarkers. They can potentially be used in CRC management, namely, in the diagnosis and treatment of tumor response access and in tumor aggressiveness prediction.

#2215 Early molecular and cellular features of aortic remodeling in a mild CKD-MBD model with low bone turnover

Abstract Background and Aims Vascular calcification associated with a maladaptive bone response is common in CKD and is a major cause of mortality (up to 60% depending on CKD stage). Alterations in several intracellular signaling pathways have been reported during the cellular phenotype transition and vascular calcification, however the initial phases of vascular remodeling in early CKD-MBD remain poorly understood. The aim of this study was to investigate the early molecular and cellular features of aortic remodeling prior to calcification in a model of mild CKD-MBD with low bone turnover. Method We induced CKD-MBD by 3/4 nephrectomy (Nx, n = 8) in adult male spontaneously hypertensive rats (SHR) with normal phosphate (Pi) intake (0.6%). Controls were sham-operated Wistar rats (n = 8) and SHR (n = 8). Chronic kidney injury and Pi exchange parameters, serum levels of calciprotein particles (CPPs), intact PTH, intact FGF23, dickkopf-1 and sclerostin, static bone histomorphometry, aortic morphology (H&amp;E, Masson's trichrome, calcein, von Kossa stain), CD31, aSMA, nestin, Col1a1, PDGFR-beta, PiT1, LGR4 and intracellular signaling molecules—phospho-ERK1/2, active (non-phospho) beta-catenin, Hes1, Gli1 were analyzed by IHC with quantitative morphometry and IF after 4 months. Confocal microscopy was performed at the Centre for Collective Use of the Pavlov Institute of Physiology, Russian Academy of Sciences (Zeiss LSM 710). Results The study found that Nx rats with chronic kidney injury comparable to human CKD S2 exhibited lower bone turnover (Fig. 1). The Nx group had higher serum levels of Pi and CPPs vs. control group, but there were no differences in Pi-regulatory factors (Figs 1, 2b). Additionally, the Nx group showed aorta remodeling, which was characterized by an increase in intima thickness, cellularity, and collagen accumulation in the medial layer (Figs 1, 2a). The histological parameters of intimal remodeling and perivascular fibrosis were found to be directly correlated with serum levels of Pi and CPPs. In Nx, there was a decrease in medial αSMA expression accompanied by an increase in phospho-ERK1/2, PiT1, nestin, Gli1, beta-catenin, dickkopf-1, and an decrease in Hes1 immunomorphological staining (Figs 1, 2a, c). αSMA-negative cells demonstrated the expression of osteogenesis-related molecules, such as phospho-ERK1/2 (Fig. 2a, c), and occasionally, RunX2 (Fig. 2a). Phospho-ERK1/2 and PiT1 were found to co-localize in Nx (Fig. 2c). Intimal remodeling was observed, characterized by increased beta-catenin and nestin expression (Fig. 2c). Conclusion In mild CKD-MBD with low bone turnover, early intimal and medial aortic remodeling was associated with higher serum Pi and CPPs levels, and upregulation of PiT1, ERK1/2. In addition, other signals likely related to osteogenesis (RunX2, LGR4) and regulation of vascular progenitor cells (Nestin, Wnt, Notch, Hedgehog) may be implicated.

YAP prevents senescence of dermal fibroblast and inhibits melanogenesis via paracrine effect of DKK1.

Senile skin hyperpigmentation displays remarkable histopathological features of dermal aging. The crosstalk between melanocytes and dermal fibroblasts plays crucial roles in aging-related pigmentation. While senescent fibroblasts can upregulate pro-melanogenic factors, the role of anti-melanogenic factors, such as dickkopf1 (DKK1), and the upstream regulatory mechanism during aging remain obscure. This study investigated the roles of yes-associated protein (YAP) and DKK1 in the regulation of dermal fibroblast senescence and melanogenesis. Our findings demonstrated decreased YAP activity and DKK1 levels in intrinsic and extrinsic senescent fibroblasts. YAP depletion induced fibroblast senescence and downregulated the expression and secretion of DKK1, whereas YAP overexpression partially reversed the effect. The transcriptional regulation of DKK1 by YAP was supported by dual-luciferase reporter and chromatin immunoprecipitation assays. Moreover, YAP depletion in fibroblasts upregulated Wnt/β-catenin in melanocytes and stimulated melanogenesis, which was partially rescued by the re-supplementation of DKK1. Conversely, overexpression of YAP in senescent fibroblasts decreased Wnt/β-catenin levels in melanocytes and inhibited melanogenesis. Additionally, reduced levels of YAP and DKK1 were verified in the dermis of solar lentigines. These findings suggest that, during skin aging, epidermal pigmentation may be influenced by YAP in the dermal microenvironment via the paracrine effect of DKK1.

Author Correction: The clinical significance and diagnostic value of serum Dickkopf1 and CKAP4 levels in patients with gastric cancer: a prospective study.

Correction to: Eur Rev Med Pharmacol Sci 2023; 27 (20): 10031-10040-DOI: 10.26355/eurrev_202310_34183-PMID: 37916373-published online on October 27, 2023. After publication, the authors found a mistake in Table I. Under Table I, the following sentence "HR: hazard ratio. CI: confidence interval. SCC: squamous cell carcinoma. FIGO: International Federation of Gynecology and Obstetrics. DFS: disease-free survival. OS: overall survival. p<0.05 and p<0.01 values were accepted for the significance level of the test" has been mistakenly inserted and must be removed. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34183.

Abstract 3925: Cancer-associated fibroblast-derived Dickkopf-1 impairs anti-tumor immunity in breast cancer by suppressing NK cell-mediated cytotoxicity

Abstract Despite early diagnosis, 10-20% of breast cancer patients experience metastatic disease within 5-10 years. While it is established that breast cancer cells have the capacity to evade immune responses, the mechanisms driving this evasion remain elusive. Therefore, finding ways to enhance anti-tumor immunity is crucial to improve patient outcomes. Dickkopf-1 (DKK1) is a Wnt inhibitor whose levels correlate with poor prognosis and decreased immune infiltration in various cancers. In this study, we used mice orthotopically injected with the PyMT, EO771, and 4T1 breast cancer lines. In all models, we found elevated DKK1 serum levels, and its neutralization with an αDKK1 Ab resulted in a significant reduction in primary tumor growth but also in metastatic dissemination. To identify the source of DKK1, we examined its expression in the tumor. DKK1 was detected in stromal cells with a fibroblast-like morphology but not in cancer cells or immune infiltrates. Co-staining confirmed colocalization between DKK1 and the CAF marker αSMA. To address the role of CAF-derived DKK1, we specifically deleted DKK1 in CAFs by generating FSP1CreDkk1fl/fl and αSMACreERT2Dkk1fl/fl mice. Both models showed a significant reduction in primary tumor growth while maintaining comparable serum DKK1 levels, indicating locally produced DKK1 supports tumor growth. To understand how DKK1 promotes tumor progression, we conducted bulk RNAseq of tumor cells isolated from IgG or αDKK1 treated mice. While no changes related to cell viability or cell cycle were observed, immune response-related genes were upregulated in αDKK1-treated cells. In support of this, αDKK1 did not reduce tumor growth in NSG immune-compromised mice. To pinpoint the immune cell targeted by DKK1, we depleted T, NK cells, or macrophages in WT tumor-bearing mice treated with αDKK1. Remarkably, only NK cell depletion negated αDKK1 anti-tumor effects. In vitro assays further demonstrated that rDKK1 or the presence of CAFs reduced NK cell cytotoxicity against tumor cells while αDKK1 restored it. To assess whether DKK1 levels correlated with tumor progression and immune suppression in breast cancer patients, we analyzed DKK1 serum levels and circulating NK cells at the diagnosis of metastatic bone disease and 15-18 months after standard care. DKK1 levels were significantly elevated in patients with progressive bone disease compared to those with stable disease. Importantly, NK cells from the progressive disease cohort had reduced perforin and granzyme B expression at the follow-up visit compared to baseline, indicating reduced cytotoxicity. Furthermore, rDKK1 reduced perforin in NK cells from healthy donors. In sum, our data show DKK1 is an important regulator of breast cancer progression, and we report for the first time DKK1 directly impairs NK cell cytotoxicity, creating an immune suppressive environment resistant to treatment. Citation Format: Seunghyun Lee, Biancamaria Ricci, Roberta Faccio. Cancer-associated fibroblast-derived Dickkopf-1 impairs anti-tumor immunity in breast cancer by suppressing NK cell-mediated cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3925.

Changes in Dickkopf-1, but Not Sclerostin, in Gingival Crevicular Fluid Are Associated with Peroral Statin Treatment in Patients with Periodontitis.

Background and Objectives: Periodontitis is marked by the destruction of alveolar bone. Sclerostin (SOST) and dickkopf-1 (DKK-1) act as inhibitors of the Wingless-type (Wnt) signaling pathway, a key regulator of bone metabolism. Recent studies have suggested that statins play a role in bone resorption and formation by influencing Wnt signaling. The aim of this study was to determine the levels of SOST and DKK-1 in periodontal patients with and without peroral statins treatment in their therapy. Materials and Methods: A total of 79 patients with diagnosed periodontitis were divided into two groups: 39 patients on statin therapy (SP group) and 40 patients without statin therapy as a control group (P group). The periodontal clinical examination probing (pocket) depth (PD) and gingival recession (GR) were measured, and approximal plaque was detected, while vertical and horizontal bone resorption was measured using a panoramic radiograph image. Clinical attachment loss (CAL) values were calculated using PD and GR values. Gingival crevicular fluid (GCF) was collected and used for measuring SOST and DKK-1 levels. A questionnaire was used to assess lifestyle habits and statin intake. Patients' medical records were used to obtain biochemical parameters. Results: There was no significant difference in sclerostin concentration between the SP and P group. DKK-1 values were significantly higher in the SP group compared to the control group (p = 0.04). Also, PD (p = 0.001) and GR (p = 0.03) were significantly higher in the SP group. The level of DKK-1 had a positive relationship with the PD, the greater the PD, the higher the level of DKK-1 (Rho = 0.350), while there was no significant association with other parameters. Conclusions: Peroral statins in periodontal patients are associated with GCF levels of DKK-1 but not with sclerostin levels.

Close negative correlation of local and circulating Dickkopf-1 and Sclerostin levels during human fracture healing

Wnt signaling is critically involved in fracture healing. Existing data predominantly relies on rodent models. Here, we explored local and circulating Dickkopf-1 (DKK1) levels in patients with respect to fracture healing and explore its association to sclerostin (SOST). 69 patients after surgical stabilization of long bone fractures of which six patients had impaired fracture healing were included in this study. Life-style and patient related factors with a known effect on DKK1 and SOST were recorded. DKK1 and SOST concentrations were measured using enzyme-linked immunosorbent assay (ELISA) at the fracture site and in circulation. DKK1 and SOST showed a close inverse correlation. In fracture hematoma and immediately after trauma DKK1 levels were significantly reduced while SOST levels were significantly increased, compared to healthy control. Postoperatively, DKK1 peaked at week 2 and SOST at week 8, again demonstrating a close negative correlation. Age and smoking status affected the balance of DKK1 and SOST, while type 2 diabetes and sex did not demonstrate a significant influence. Early postoperative elevation of SOST without compensatory DKK1 decrease was associated with fracture non-union in younger patients (< 50a). The close inverse correlation and very rapid dynamics of DKK1 and SOST locally as well as systemically suggest their critical involvement during human fracture healing. Importantly, as immediate compensatory feedback mechanism are apparent, we provide evidence that dual-blockade of DKK1 and SOST could be critical to allow for therapeutic efficiency of Wnt targeted therapies for fracture healing.

The predictive value of serum Dickkopf-1, Dickkopf-3 level to coronary artery disease and acute coronary syndrome

BackgroundPrevious studies have already confirmed the association between Dickkopf (Dkk) protein and the occurrence and progression of atherosclerosis. However, there is limited clinical evidence regarding the serum levels of Dickkopf-1 (Dkk1) and Dickkopf-3 (Dkk3) in relation to atherosclerotic cardiovascular disease (ASCVD), particularly acute coronary syndrome (ACS). Materials and methodsA total of 88 healthy volunteers and 280 patients with coronary artery disease (CAD) undergoing coronary angiography for angina between October 2021 and October 2022, including 96 cases of stable angina (SA), 96 of unstable angina (UA) and 88 of acute myocardial infarction (AMI) were included finally. The serum concentrations of Dkk1 and Dkk3 were measured using electrochemiluminescence of Meso Scale Discovery. The predictive value of single or combined application of serum Dkk1 and Dkk3 in CAD and ACS were evaluated. ResultsThe serum levels of Dkk1 were significantly higher in the SA group, UA group, and AMI group compared to the control group. Multivariable logistic regression analysis demonstrated that elevated serum Dkk1 levels were independent predictive factors for increased risk of CAD and ACS (OR = 1.027, 95%CI = 1.019–1.034, p < 0.001; OR = 1.045, 95%CI = 1.028–1.053, p < 0.001, respectively). Receiver operating characteristic curve (ROC) analysis showed that the optimal cutoff value of serum Dkk1 for predicting ACS was 205 ng/dl, with a sensitivity of 82.6% and specificity of 96.6%. The area under the curve (AUC) was 0.930 (95%CI: 0.899–0.961, p < 0.001). Regarding Dkk3, serum Dkk3 levels were elevated in CAD patients compared to the healthy control group, and significantly higher in ACS patients compared to SA patients. Serum Dkk3 was significantly associated with increased risk of CAD and ACS (OR = 1.131, 95%CI = 1.091–1.173, p < 0.001; OR = 1.201, 95%CI = 1.134–1.271, p < 0.001, respectively). ROC curve analysis showed that the optimal cutoff value of serum Dkk3 for predicting ACS was 50.82 ng/ml, with a sensitivity of 85.9% and specificity of 87.5%. The AUC was 0.925 (95%CI: 0.894–0.956, p < 0.001). When serum Dkk1 and Dkk3 are combined as predictive factors for ACS, the AUC was 0.975. ConclusionSerum levels of Dkk1 and Dkk3 are significantly associated with an increased risk of CAD and ACS, and they possess predictive value for CAD and ACS. The combination of serum Dkk1 and Dkk3 is a superior predictive factor for CAD and ACS.

Aberrant DNA Methylation Profile of Dickkopf-1 in Ankylosing Spondylitis.

In recent years, the impact of methylation modifications on Dickkopf-1 (DKK1) in relation to ankylosing spondylitis (AS) has remained elusive. Our objective was to investigate the potential link between DKK1 methylation patterns and transcript levels and AS susceptibility. DNA methylation level of DKK1 was measured in 82 AS and 82 healthy controls (HCs) using targeted bisulfite sequencing. In addition, the transcript level of DKK1 in peripheral blood mononuclear cells from 35 AS patients and 35 HCs was detected using real-time quantitative transcription-polymerase chain reaction. Our study showed that the DKK1 was significantly hypomethylated in AS patients (P < 0.001). The Receiver operating characteristic curve (ROC) showed that DKK1 methylation may be a potential biomarker. The results showed that the difference in DKK1 transcript levels between AS and HCs was not statistically significant. Further analysis showed that DKK1 methylation levels were positively correlated with age and negatively correlated with C-reactive protein levels, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR). The methylation level of DKK1 in PBMC of AS patients was significantly lower than that of HCs, and DKK1 methylation may be associated with susceptibility to AS. In addition, DNA methylation levels of DKK1 were negatively correlated with the level of inflammation in AS patients.

β-Nicotinamide Mononucleotide Promotes Cell Proliferation and Hair Growth by Reducing Oxidative Stress.

β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease therapeutic, due to its medicinal properties. The effects of NMN on the growth of mouse hair were observed after hair removal. The results indicated that NMN can reverse the state of hair follicle atrophy, hair thinning, and hair sparsity induced by dihydrotestosterone (DHT), compared to that of minoxidil. In addition, the action mechanisms of NMN promoting hair growth in cultured human dermal papilla cells (HDPCs) treated with DHT were investigated in detail. The incubation of HDPCs with DHT led to a decrease in cell viability and the release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1Beta (IL-1β) and tumor necrosis factor Alpha (TNF-α). It was found that NMN can significantly lower the release of inflammatory factors induced by DHT in HDPCs. HDPCs cells are protected from oxidative stress damage by NMN, which inhibits the NF-κB p65 inflammatory signaling pathway. Moreover, the levels of androgen receptor (AR), dickkopf-1 (DKK-1), and β-catenin in the HDPCs were assessed using PCR, indicating that NMN can significantly enhance the expression of VEGF, reduced IL-6 levels and suppress the expression of AR and DKK-1, and notably increase β-catenin expression in DHT-induced HDPCs.

Platelet-derived growth factor subunit-B mediating the effect of dickkopf-1 on acute myocardial infarction risk: a two-step Mendelian randomization study.

Previous studies have indicated a potential connection between plasma levels of Dickkopf-1 (DKK1) and platelet-derived growth factor subunit-B (PDGF-B) with the development of atherosclerosis. However, the causal relationship between DKK1, PDGF-B, and the risk of acute myocardial infarction (AMI) is yet to be established. To address this research gap, we conducted Mendelian randomization (MR) and mediation analyses to investigate the potential mediating role of PDGF-B in the association between DKK1 and AMI risk. Summary statistics for DKK1 (n = 3,301) and PDGF-B (n = 21,758) were obtained from the GWAS meta-analyses conducted by Sun et al. and Folkersen et al., respectively. Data on AMI cases (n = 3,927) and controls (n = 333,272) were retrieved from the UK Biobank study. Our findings revealed that genetic predisposition to DKK1 (odds ratio [OR]: 1.00208; 95% confidence interval [CI]: 1.00056-1.00361; P = 0.0072) and PDGF-B (OR: 1.00358; 95% CI: 1.00136-1.00581; P = 0.0015) was associated with an increased risk of AMI. Additionally, genetic predisposition to DKK1 (OR: 1.38389; 95% CI: 1.07066-1.78875; P = 0.0131) was linked to higher PDGF-B levels. Furthermore, our MR mediation analysis revealed that PDGF-B partially mediated the association between DKK1 and AMI risk, with 55.8% of the effect of genetically predicted DKK1 being mediated through genetically predicted PDGF-B. These findings suggest that genetic predisposition to DKK1 is positively correlated with the risk of AMI, and that PDGF-B partially mediates this association. Therefore, DKK1 and PDGF-B may serve as promising targets for the prevention and treatment of AMI.

The assessment of Dickkopf-1 and Dickkopf-2 protein concentration in different subtypes of non-small cell lung cancer subtypes.

Lung cancer is one of the most prevalent cancers worldwide. Dickkopf-1 (DKK-1) and -2 (DKK-2) are important proteins for the regulated Wnt signalling pathway. Alternations in the Wnt pathway are associated with tumour progression. The aim of the study was to analyse the concentration of DKK-1 and DKK-2 in tumour and matched non-tumour (NT) samples of 65 patients with non-small cell lung cancer (NSCLC), including 3 subtypes: adenocarcinoma (AC), squamous cell carcinoma (SCC), and large cell carcinoma (LCC). The protein concentration was measured by enzyme-linked immunosorbent assay (ELISA) in homogenates. The difference between the level of DKK-1 in tumour and NT specimens was not significant for the whole NSCLC group and SCC and LCC subtype, while in AC samples they were significantly higher (p = 0.028). The highest concentration of DKK-1 was found in the advanced NSCLC samples, with the T4 parameter as well as stage III. Significantly decreased DKK-2 concentrations were detected in all NSCLC subtypes (p < 0.05). Moreover, the DKK-2 level was higher in non-smokers than in smokers. The results indicate that concentrations of DKKs were different in relation to subtypes as well as clinical and socio-demographic parameters. The concentration of DKKs could be associated with the progression of NSCLC. We suggest that DKK-1 could play an oncogenic role in AC, while DKK-2 could be a tumour suppressor in all NSCLC subtypes. Dickkopf-1 and DKK-2 proteins could have differential roles in the Wnt signalling pathway, which is important in many cellular processes, such as proliferation and apoptosis.

Clinical importance of SUPAR and Dickkopf-1 level in the etiology of pleural effusion

Clinical importance of SUPAR and Dickkopf-1 level in the etiology of pleural effusion

Biomarkers of disability worsening in inactive primary progressive multiple sclerosis

ObjectiveTo investigate serum biomarkers of progression in inactive primary progressive multiple sclerosis (PPMS). MethodsWe measured protein biomarkers (growth differentiation factor-15 (GDF-15), dickkopf-1 (DKK-1), neuron specific enolase (NSE) and cathepsin-D) in serum samples from 39 patients with inactive PPMS included in a clinical trial enrolling people with PPMS (clinicaltrials.gov identifier NCT02913157) and investigated the association of these biomarker levels with clinical disability at baseline and during follow-up. We then performed a meta-analysis of publicly available transcriptomic datasets to investigate the gene expression of these biomarkers in the CNS in progressive MS. ResultsWhen compared with healthy controls, people with PPMS had higher serum levels of GDF-15, DKK-1 and cathepsin-D at baseline. These findings match those in our meta-analysis which found increased expression of GDF-15 and cathepsin-D in the CNS in progressive MS. At baseline, elevated serum DKK-1 was associated with worse Expanded Disability Status Scale (EDSS) and nine-hole peg test (9HPT) scores. None of the other biomarkers levels significantly correlated with EDSS, Timed 25-Foot Walk Test (T25FWT), 9HPT, or cognitive measures. However, serum GDF-15 and cathepsin-D were higher at baseline in participants who developed worsening disability. Our receiver operating characteristic curve showed that higher serum GDF-15 and cathepsin-D at baseline significantly discriminated between participants who worsened in T25FWT and 9HPT and those who remained stable. ConclusionsPatients with PPMS have altered levels of GDF-15, DKK-1 and cathepsin-D in serum, and GDF-15 and cathepsin-D may have predictive value in progression free of inflammatory activity in PPMS.

Impact of serum level of Dickkopf-1 in patients with Lupus nephritis

Impact of serum level of Dickkopf-1 in patients with Lupus nephritis

The clinical significance and diagnostic value of serum Dickkopf1 and CKAP4 levels in patients with gastric cancer: a prospective study.

Gastric cancer is diagnosed at an advanced stage in most patients, and the prognosis is poor. Novel biochemical markers of high diagnostic value for the detection of the disease are therefore important. Dickkopf1 (DKK1) and cytoskeleton-associated protein 4 (CKAP4) have been extensively studied as biomarkers in cancer patients. Serum DKK1 and CKAP4 levels in 58 patients with gastric cancer and 41 healthy controls were examined using an ELISA kit in this prospective study. The patients were subdivided into groups based on pathological TNM staging and histological grades. Serum levels of both proteins in the patients with gastric cancer were measured preoperatively, 10 and 30 days after surgery. Serum DKK1 and CKAP4 levels were significantly higher in the gastric cancer group compared to the healthy controls (p<0.05). Serum levels of both proteins increased in line with the pathological stage and histological grade of the gastric cancer. Serum CKAP4 and DKK1 levels decreased after surgical resection. Both serum levels also decreased significantly on day 30 after surgery compared to day 10 (p<0.05). Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) positivity rates were below 20% in the gastric cancer group, while the diagnostic value (sensitivity and specificity) of serum CKAP-4 and DKK1 exceeded 80%. DKK1 and CKAP4 are biomarkers of high diagnostic value that can be used to diagnose and predict the severity of gastric cancer. These proteins can also be employed for disease monitoring after surgical resection. The diagnostic value of these proteins is higher than that of biomarkers such as CEA and CA19-9, which are routinely used in clinical practice.

The role of miR-433-3p in vascular calcification in type 2 diabetic patients: targeting WNT/β-Catenin and RANKL/RANK/OPG signaling pathways

BackgroundVascular calcification (VC) is a major predictor of cardiovascular diseases that represent the principal cause of mortality among type-2 diabetic patients. Accumulating data suggest the vital role of some microRNAs on vascular calcification as an epigenetic regulator. Thus, we assessed herein, the role of serum miR-433-3p in vascular calcification in type-2 diabetic patients.MethodsTwenty healthy subjects (control group) and forty diabetic patients (20 without VC and 20 with VC) were involved in the study. miR-433-3p gene expression was measured. Runx2, Dickkopf-1 (DKK1), β-catenin, Receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) levels in serum were assessed by ELISA technique.ResultsDiabetes patients had significantly lower levels of miR-433-3p expression in comparison to the control group, with the lowest levels being found in diabetic patients with VC. Furthermore, Runx2, β-catenin, and RANKL levels were significantly increased with concomitant lower DKK1 and OPG levels detected in the two diabetic groups especially those with VC.ConclusionCollectively, the study documented that down-regulation of miR-433-3p may contribute to the development of VC through activating WNT/β-Catenin and RANKL/RANK/OPG signaling pathways.