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Objective:Both type 1 diabetes and type 2 diabetes are associated with abnormal bone metabolism, but they have different pathogenic mechanisms. Sclerostin(SOST), Dickkopf-related protein 1(DKK-1), and irisin are newly discovered factors involved in the regulation of bone metabolism. This study aims to compare the differences in serum levels of SOST, DKK-1, and irisin between patients with type 1 diabetes and type 2 diabetes.Methods:This cross-sectional study included 101 patients with type 1 diabetes who visited the Endocrinology Department of Peking Union Medical College Hospital from 2017 to 2019, as well as 55 patients with type 2 diabetes and 59 individuals with normal glucose tolerance who were confirmed through an oral glucose tolerance test as part of the Beijing Changping Community Type 2 Diabetes Management Program from 2014 to 2015. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of SOST, DKK-1, and irisin.Results:There were more female participants than male participants, with an average age of 49 years. The group with type 1 diabetes had a longer duration of illness( P<0.001) and higher HbA 1C levels( P<0.001) compared to the group with type 2 diabetes, and there was no statistical difference in age between the two groups. Both the type 1 diabetes and type 2 diabetes groups had lower levels of serum procollagen type 1 N-terminal propeptide(P1NP) compared to the control group [(8 579±400)pg/mL, (7 268±552)pg/mL vs(10 051±618)pg/mL, P=0.039, P=0.001]; But the β isomer of C-terminal cross-linking telopeptide of type 1 collagen(β-CTX) showed no statistical difference compared to the control group. Patients with type 1 diabetes and type 2 diabetes had higher SOST than controls [(129.7±6.8)pg/mL, (104.8±6.8)pg/mL vs(85.9±5.3)pg/mL, P<0.001, P=0.030], the differences between the type 1 diabetes group and the control group lost statistical significance after adjusting for factors such as fasting blood glucose and lipid levels. There was no significant difference in SOST between type 1 diabetes and type 2 diabetes groups. There was no significant difference in DKK-1 among three groups, but DKK-1 in type 1 diabetes group was lower or tended to be lower than that in type 2 diabetes group. Serum irisin in patients with type 1 diabetes was higher than that in controls and patients with type 2 diabetes[(16.6±0.7)ng/mL vs (9.6±0.6)ng/mL, (9.8±0.6)ng/mL, both P<0.001], but there was no significant difference in irisin level between type 2 diabetes and controls. Conclusions:Patients with both type 1 and type 2 diabetes showed inhibition of the bone formation marker P1NP, while the bone resorption marker β-CTX did not significantly change. SOST levels were elevated or showed an increasing trend in both type 1 and type 2 diabetes patients, which may be related to the inhibition of bone formation. Additionally, type 1 diabetes patients had increased levels of irisin, which may be involved in abnormal bone turnover.
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Objective:To investigate the correlation between serum recombinant sclerostin (SOST) and dickkopf-related protein 1 (DKK-1) levels and bone metabolism indexes in patients with osteoporosis after differentiated thyroid cancer surgery.Methods:A total of 110 patients diagnosed with osteoporosis after differentiated thyroid cancer surgery were recruited as the study group, and another 110 patients without osteoporosis diagnosed after differentiated thyroid cancer surgery were recruited as the control group. The general data, bone mineral density, serum SOST, DKK-1 levels and bone metabolism indicators N-terminal propeptide of type I procollagen (PINP), bone alkaline phosphatase (BALP), beta-isomerized C-telopeptide (β-CTX), 25-hydroxyvitamin D3 [25- (OH) D3] levels were compared between the two groups. The correlation between serum SOST, DKK-1 levels and bone metabolism indexes was analyzed, and the risk factors affecting the formation of osteoporosis were explored.Results:The T value of bone mineral density in the study group (-3.27±0.92) was significantly lower than that in the control group (-1.23±0.27, t=22.32, P<0.001). The serum SOST (15.84±1.34, t=32.53, P<0.001) and DKK-1 (5.96±1.40, t=4.82, P<0.001) levels in the study group were significantly higher than those in the control group (SOST: 10.24±1.21, DKK-1: 5.05±1.40). The serum PINP (40.95±9.84, t=7.59, P<0.001), BALP (23.14±5.26, t=5.06, P<0.001) and β-CTX (1.07±0.54, t=4.96, P<0.001) in the study group were significantly higher than those in the control group (31.48±8.64, 19.64±4.99, 0.78±0.29), and the 25- (OH) D3 level (13.68±4.49) was significantly lower than that of the control group (18.31±5.72, t=6.68, P<0.001). Serum SOST was positively correlated with PINP ( r=0.33, P=0.001), BALP ( r=0.23, P=0.016) and β-CTX ( r=0.19, P=0.046), but not with 25- (OH) D3 ( r=-0.09, P=0.349). Serum DKK-1 was positively correlated with PINP ( r=0.19, P=0.044), BALP ( r=0.26, P=0.007) and β-CTX ( r=0.21, P=0.028), but not with 25- (OH) D3 ( r=-0.16, P=0.088). Serum SOST and DKK-1 levels were independent risk factors for osteoporosis (all P<0.05) . Conclusion:Serum SOST and DKK-1 levels are independent risk factors for the formation of osteoporosis, which are significantly positively correlated with bone metabolism indexes PINP, BALP, and β-CTX in patients with osteoporosis after differentiated thyroid cancer surgery.
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BACKGROUND@#Lung cancer is the most common malignant tumor in China, lung adenocarcinoma (LUAD) is the main type of lung cancer, which is a serious threat to people's life and health. At present, there are fewer studies on the role of Dikkopf1 (DKK1) in lung adenocarcinoma. The aim of this study was to investigate the role and potential prognostic value of DKK1 in the development of lung adenocarcinoma by bioinformatics methods.@*METHODS@#Several databases, such as genotype-tissue expression (GTEx), The Cancer Genome Atlas (TCGA) and tumor-immune system interactions database (TISIDB), were used to analyze the expression, clinicopathological features, immune cell infiltration, prognosis and methylation of DKK1 in lung adenocarcinoma. Then, linked immune cell infiltration Omics database was used to analyze the co-expressed genes of DKK1 and their functional enrichment. Finally, 59 pathological samples of paraffin-embedded lung adenocarcinoma patients who underwent surgery at the Affiliated Cancer Hospital of Xinjiang Medical University between 2016 and 2017 were collected for the validation of the prognostic value of expression by immunohistochemistry (IHC) test.@*RESULTS@#The results of bioconfidence analysis showed that the expression level of DKK1 in lung adenocarcinoma tissues was higher than that in normal tissues, the expression in advanced cancers was higher than that in early stages, and the experimental validation revealed that among 59 cases of lung adenocarcinoma, there were 15 cases of negative expression (25.4%), 18 cases of weakly positive expression (30.5%), and 26 cases of strongly positive expression (44.1%). The different expression of DKK1 is related to methylation, prognosis and the activities of various immune cells. Functional enrichment shows that DKK1 may be involved in skin development and cell-substrate junction, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis shows that DKK1 is related to ABC transporters. Bioinformatics analysis and clinical case specimens showed that high DKK1 expression was associated with poorer prognosis in patients with lung adenocarcinoma.@*CONCLUSIONS@#High expression of DKK1 in lung adenocarcinoma is associated with poor prognosis. DKK1 is closely associated with tumor immune cell infiltration and pathways. DKK1 can be considered as a potential prognostic marker and a novel target for immunotherapy of lung adenocarcinoma.
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AIM: To scrutinize the role of the Wnt/β-catenin signaling pathway in the epithelial-mesenchymal transition(EMT)of lens epithelial cells under hypoxic conditions, and to further analyze the effect of Dickkopf-1(DKK-1)expression on EMT of lens epithelial cells.METHODS: Human lens epithelial cells(HLEB3 cells)were propagated in vitro and then separated into two groups: one exposed to standard oxygen levels, added DMEM culture solution containing 10% FBS(normoxic group)and another subjected to low oxygen levels(hypoxic group). The hypoxic condition was emulated by applying a concentration of 100 μmol/L cobalt chloride(CoCl2)for 6, 12, 24, and 48h. The utilization of immunofluorescence staining enabled the detection of Wnt3a and DKK-1 expressions, along with the expression and localization of β-catenin protein in these groups. The expression of DKK-1 mRNA was discerned by quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: Immunofluorescence assays indicated an escalating trend in the Wnt3a and DKK-1 protein expression, which corresponded with the increasing duration of hypoxia. Likewise, an intensified nuclear accumulation of β-catenin protein was observed to be directly proportional to the length of hypoxia treatment. The qRT-PCR demonstrated that the difference in DKK-1 mRNA expression between the normoxic group and the group exposed to hypoxia for 6h was not statistically significant(P>0.05), whereas the DKK-1 mRNA expression of the 12, 24, and 48h hypoxia groups were significantly increased(P<0.001).CONCLUSION: Hypoxia can activate Wnt/β-catenin pathway in lens epithelial cells and induce the expression of DKK-1, thus regulating the Wnt/β-catenin pathway and affecting the EMT process.
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Objective To explore the expression and significance of serum DKK1 in patients with gastric cancer. Methods We selected 170 gastric cancer patients (gastric cancer group) and 170 subjects with non-gastric cancer during the same period (control group). ELISA was used to detect the DKK1 level. The ROC curve was used to evaluate the diagnostic performance, and we analyzed the relation between DKK1 level and age, gender, family history of gastric cancer, cigarette smoking, alcohol consumption, tumor size, TNM stage, infiltration depth, lymph node metastasis, liver metastasis, vascular invasion, perineural invasion. Results The serum DDK1 level in GC patients was higher than that in control group (P < 0.0001). ROC curve showed that the possible optimal cut-off value of DKK1 for gastric cancer patients was 167.8 pg/ml, AUC was 0.908, sensitivity was 80.59%, and specificity was 84.71%. There was no significant relation between the serum DKK1 level and age, gender, family history of gastric cancer, cigarette smoking, alcohol consumption, tumor size, liver metastasis, vascular invasion or distant metastasis (all P > 0.05). However, DKK1 level was significantly related with TNM stage, infiltration depth, lymph node metastasis and perineural invasion (all P < 0.05). Conclusion Serum DKK1 level is higher in gastric cancer patients than that of control group and related with the severity of lesions, which indicates that serum DKK1 may be a potential biomarker for gastric cancer screening.
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@#[Abstract] Objective: To explore the expression and regulation mechanism of Dickkopf-1 (DKK1) in head and neck squamous cell carcinoma (HNSCC) tissues. Methods: Based on the TCGA database, the relationship of DKK1 expression in HNSCC tissues and its methylation site with patients’prognosis was analyzed. GO and KEGG gene enrichment method were used to analyze the signaling pathways of DKK1 enrichment. STRING was used to analyze the interaction between DKK1 protein and other proteins. TargetScan was used to analyze the miRNAs that regulate the expression of DKK1, and the transcription factors of DKK1 were analyzed with the TRRUST website. Results: DKK1 gene was highly expressed in HNSCC tissues (P<0.01), and its expression level was significantly correlated with the HPV status, age, pathological grade, and clinical stage of patients (all P<0.05); the prognosis of HNSCC patients with high DKK1 expression was poorer than those with low DKK1 expression (P<0.01). There were 19 methylation sites in DKK1, 12 of which were significantly different between cancer tissues and normal tissues (P<0.05), and 11 sites were significantly related to the prognosis of HNSCC (P<0.05). In addition, miRNA, circRNA, lincRNA and transcription factors, etc. also participated in the regulation of DKK1. A total of 5 DKK1-related PPI networks that may involve in the occurrence, development, invasion and metastasis of HNSCC were obtained. Conclusion: DKK1 is highly expressed in HNSCC tissues and is a risk factor for poor prognosis of HNSCC patients. DKK1 plays an important role in the pathogenesis of HNSCC and is expected to become a potential target for HNSCC treatment.
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@# Objective： ：To study the effect of silencing DKK1 (Dickkopf1) gene on the proliferation, cell cycle and apoptosis of gastric cancer AGS cells and the action mechanism. Methods： ：The DKK1-shRNA vector was constructed and transfected into AGS cells. The stably transfected cell lines were screened. The total protein and RNAof the transfected cells were extracted and the mRNAand protein expressions of DKK1 were detected by qPCR and WB, respectively. The experiment was divided into blank control group (Control), negative control group (shNC) and DKK1 silence group (DKK1-shRNA). CCK8 assay was used to detect the proliferation ofAGS cells of each group cultured for 0, 24, 48, 72, 96, 120 and 144 h, and flow cytometry was used to analyze the cell cycle and apoptosis in each group. The relationship between DKK1 and clinicopathological features of gastric cancer was analyzed after searching HPA database. Results：The gastric cancer AGS cells with stable DKK1 gene knockdown was successfully established, and it was confirmed that the mRNA and proteinexpressions of DKK1 in DKK1-shRNA group decreased by 72% and 47%, respectively, compared to shNC group (all P<0.05). The cell proliferation curve showed that, the cell proliferation in DKKl-shRNAgroup significantly decreased after 72 hour of culture compared with that in control and shNC groups (P<0.05). The cell number of S phase decreased from 32.06% to 25.87%, while the number of G2/M phase increased from 8.49% to 21.26% compared with shNC group (all P<0.05). The number of apoptotic cells also statistically increased from 10.34% to 20.65% (all P<0.05). The data of HPAdatabase showed that DKK1 mRNAlevel in gastric cancer tissues was significantly higher than that in normal tissues, and the high expression of DKK1 mRNAwas negatively correlat ed with the survival rate of gastric cancer patients. Conclusion: : Silencing DKK1 gene can inhibit the proliferation of gastric cancer cells, arrest cells in G2/M phase and promote cell apoptosis. DKK1 plays a pro-carcinogenic effect in gastric cancer.
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Objective To investigate the expression of Wnt/β-catenin signal antagonist DKK1 protein in callus of distraction gap during mandibular distraction osteogenesis (MDO).Methods Twenty four healthy New Zealand rabbits were randomly divided into distraction group,fracture control group,with twelve rabbits each,respectively.In distraction group,bilateral mandibular distraction models were established.In control group,after bilateral mandibular osteotomy,the two bone fragments were fixed by titanium plate and screws with a 5 mm gap.The expression of DKK1 in the distracted calluses was analyzed by cell digital imaging software.Results Expression of DKK1 was colocalized in the nucleus and cytoplasm of osteoblasts,fibroblasts,cartilageand newly embedded osteocytes.The expression of DKK1 increased following distraction activated after surgery,peaked at 10 days after surgery,the population of cells that stained for DKK1 decreased gradually.At 31 to 38 days postoperatively,DKK1 expression reduced gradually,mainly located in the osteocyte,and both nucleus and cytoplasm were positive staining.At each time point,the expression of DKK1 in distraction group was higher than that in the control group and the difference was statistically significant (P＜0.05).Conclusions During MDO,the Wnt/β-catenin pathway is activated due to the distraction and mechanical strain on the bone.With the increased expression of Wnt-related factors,the endogenous negative feedback is enhanced to induce DKK1 expression and to regulate the activated Wnt/β-catenin pathway.This would be beneficial to the new bone formation and remodeling in the distraction gap.
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Whether and how garlic-derived -allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of -catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.
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OBJECTIVE:To study the effect of Xuchangqing-ermiaosan-santeng formula on the contents of tumor necrosis fac-tor α(TNF-α)and ossification-related factor DKK-1 in serum of model mice with arthritis,and reveal its mechanism in the treat-ment of arthritis. METHODS:60 BALB/c mice were randomly divided into normal group,model group,sulfasalazine group(posi-tive control,9 mg/kg) and Xuchangqing-ermiaosan-santeng formula low-dose,medium-dose,high-dose groups (calculated by crude drug as 11.25,22.5,45 g/kg),10 in each group. Except for normal group,other 50 mice were intraperitoneallly injected complete Freund's adjuvant + proteoglycans to induce model with arthritis. After modeling,mice in each administration group were intragastrically administrated relevant medicines,mice in normal group and model group were intragastrically administrated equal volume of normal saline,once a day,for 20 d. After administration,enzyme-linked immunosorbent assay was used to detect the contents of TNF-αand DKK-1 in serum of mice in each group,and ultrastructural changes of sacroiliac joint synovial cells were ob-served by transmission electron microscopy. RESULTS:Compared with normal group,TNF-α content in serum in model group was obviously increased,DKK-1 content was obviously decreased (P<0.05);sacroiliac joint synovial cells showed hyperplasia, organellar deformation,mitochondrial swelling and other pathologic damage. Compared with model group,TNF-α contents in se-rum in each administration group were obviously decreased(P<0.05 or P<0.01);except for sulfasalazine group,the DKK-1 con-tent of mice in other administration groups were obviously increased (P<0.05). Pathologic damages of sacroiliac joint synovial cells in each administration group were reduced to varying degrees,and improvement degree in Xuchangqing-ermiaosan-santeng for-mula groups was higher than sulfasalazine group. CONCLUSIONS:Xuchangqing-ermiaosan-santeng formula may inhibit the sacroil-iac arthritis and pathological ossification of model mice with arthritis by decreasing TNF-α content and increasing DKK-1 content in serum.
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Objective:To study the expression characteristics of Dickkopf1 (DKK1) in different time and space during tooth development of the postnatal mice, and to provide the theoretical basis for clarifying the mechanism of Wnt signaling pathway in regulating the tooth development.Methods:The postnatal Kunming mice at days 0.5, 6.5, 12.5, 18.5, 24.5, and 30.5 respectively after birth were selected and divided into various groups by time,three in each group.The mice in each group were sacrificed and the paraffin sections of mandibular bone including the first molar were prepared at the thickness of 5 μm, followed by HE staining and immunohistochemical staining in order to detect the expressions of DKK1 in tooth tissue and periodontal tissue.Results:At 0.5 d after birth, the mandibular first molar tooth germ was in the bell stage.At 6.5 d the enamel development of mandibular first molar was almost completed, and the epithelium root sheath extended to the root direction.At 12.5 d the dentin development of crown was completed, with the root formatted about 1/3. At 18.5 d the root had formatted about 2/3.At 24.5 d the root had reached the full length.At 30.5 d the apical foramen was narrow, and the root development was basically completed.There was no DKK1 expression at 0.5 d, but it expressed in the odontoblasts and predentin at 6.5 d. From days 12.5 to 30.5,the expressions of DKK1 were positive in periodontal ligament, alveolar bone, and cellular cementum as odontoblasts, which were gradually increased with the prolongation of time.However, no expression of DKK1 was detected in the pulp.Conclusion:DKK1 shows regular expressions at different tooth developmental stages after birth, suggesting its potential role in the growth of dentin and periodontal tissues.
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Objective The objectives of this study were to investigate the relationship between DKK1 protein expression and lymph node invasion,and prognosis in patients with intrahepatic cholangiocarcinoma.Methods From January 2005 to December 2012,78 patients with intrahepatic cholangiocarcinoma were treated with endoscopic resection.Tissue microarray of intrahepatic cholangiocarcinoma and adjacent tissues were done and biochemical indexes were measured before operation.The patients were recruited every 3 months after operation.The Kaplan-Meier method was used to analyze the recurrence-free survival curve and the overall survival curve.The Cox proportional hazards regression model was used to analyze the multivariate analysis and to determine the factors that affect the disease-free survival(RFS)and overall survival(OS).Results There were significant differences in the expression of GGT,hepatic portal lymph node invasion,Child-Pugh grade,MMP9 and DKK1 protein in the negative and positive expression of intrahepatic cholangiocarcinoma(P ＜ 0.05).The positive expression rate of DKK1 protein in intrahepatic cholangiocarcinoma was 35.90％ (28/78),and the positive expression rate of DKK1 protein in hilar cholangiocarcinoma was 14.10％ (11/78).RFS and OS in 78 cases of intrahepatic cholangiocarcinoma were 51.28％ (40/78) and 50.00％ (38/78),41.03 ％ (32/78) and 38.46％ (30/ 78),25.64％ (20/78) and 23.08％ (18/78) after surgery for 1,3 and 5 years,respectively.The results from univariate and multivariate analysis showed that GGT,CA19-9,CEA,tumor size,DKK1 and hilar lymph node invasion were the prognostic factors of OS in patients with intrahepatic cholangiocarcinoma.CEA,tumor size,DKK1 and hilar lymph node involvement were prognostic factors for RFS in patients with intrahepatic cholangiocarcinoma.DKK1 protein expression positive and negative OS curve or RFS curve showed that 5 years after intrahepatic cholangiocarcinoma patients DKK1 protein expression positive and negative OS were 28.20％ and 20.51％;RFS were 24.36％ and 21.79％.Conclusion The expression of DKK1 protein is closely related to lymph node invasion in patients with intrahepatic cholangiocarcinoma.The expression of DKK1 protein is the prognostic factor of OS and RFS in patients with intrahepatic cholangiocarcinoma.
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Objective To explore the serum expression of DKK1 protein, a Wnt signaling pathway inhibitor in patients with non-small cell lung cancer (NSCLC) and its relationship with osseous metastasis. Methods Serum DKK1 protein levels were assayed by enzyme-linked immunosorbent assay (ELISA) in NSCLC patients, including 33 NSCLC patients with osseous metastasis and 41 NSCLC patients without respectively, and 32 healthy volunteers were served as the control group. Furthermore, the differential expression of the serum DKK1 protein level between the patients and the volunteers was compared by using the variance analysis and the independent sample t test. The correlation between DKK1 expression and bone metastasis was detected by Pearson correlation analysis. Results Serum DKK1 protein level of NSCLC patients was (79.6±8.3) ng/ml, which was significantly higher than that in healthy volunteers [(21.5±6.4) ng/ml, t=13.17, P=0.001]. The serum DKK1 level in osseous metastasis group was (110.3±11.4) ng/ml, which was significantly higher than that in non-skeletal metastasis group [(60.7±10.5) ng/ml, t=14.128, P=0.003]. The positive association was observed between the DKK1 level in the peripheral blood and osseous metastasis in NSCLC patients (r=0.855, P<0.001). Conclusion The serum expression level of DKK1 protein in NSCLC patients is closely related to the osseous metastasis, which may be a predicting biomarker for the osseous metastasis.
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Objective To discuss the effect of Dickkopf-1 (DKK-1) on Wnt singal pathway during the differentiation of osteoblast in vitro.Methods The osteoblasts were obtained from the new rats and cultured in vitro.The 3 passages were divided into control group and DKK-1 group.The cells were cultured in DKK-1 and normal saline for morphogical detection,ALP activity detection and osteoblasts stained at 1 st,6th,12th,21st day.The Wnt was detected by RT-PCR.Results After cultured by the DKK-1 in vitro,the ALP and mineralization of osterblasts staining were prlonged with culture time.Compared with control group,the expression of Wnt was significantly reduced at the 21st day after induction (t =0.278,P ＜ 0.05).Conclusion DKK-1 can regulate the expression of Wnt during osteoblast differentiation,suggests that Wnt may be involved in osteoblast differentiation and can affect bone remodeling process.
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PURPOSE: Dickkopf 1 (DKK1) has been extensively investigated in mouse models of multiple myeloma, which results in osteolytic bone lesions. Elevated DKK1 levels in bone marrow plasma and serum inhibit the differentiation of osteoblast precursors. Present pharmaceutical approaches to target bone lesions are limited to antiresorptive agents. In this study, we developed a cyclized oligopeptide against DKK1-low density lipoprotein receptor-related protein (LRP) 5/6 interaction and tested the effects of the oligopeptide on tumor burden. MATERIALS AND METHODS: A cyclized oligopeptide based on DKK1-LRP5/6 interactions was synthesized chemically, and its nuclear magnetic resonance structure was assessed. Luciferase reporter assay and mRNA expressions of osteoblast markers were evaluated after oligopeptide treatment. MOPC315.BM.Luc cells were injected into the tail vein of mice, after which cyclized oligopeptide was delivered subcutaneously 6 days a week for 4 weeks. RESULTS: The cyclized oligopeptide containing NXI motif bound to the E1 domain of LRP5/6 effectively on surface plasmon resonance analysis. It abrogated the Wnt-β-catenin signaling inhibited by DKK1, but not by sclerostin, dose dependently. RT-PCR and alkaline phosphatase staining showed increased expressions of osteoblast markers according to the treatment concentrations. Bioluminescence images showed that the treatment of cyclized oligopeptide reduced tumor burden more in oligopeptide treated group than in the vehicle group. CONCLUSION: The cyclized oligopeptide reported here may be another option for the treatment of tumor burden in multiple myeloma.
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Animals , Mice , Alkaline Phosphatase , Bone Density Conservation Agents , Bone Marrow , Lipoproteins , Luciferases , Magnetic Resonance Spectroscopy , Multiple Myeloma , Osteoblasts , Plasma , RNA, Messenger , Surface Plasmon Resonance , Tail , Tumor Burden , VeinsABSTRACT
El lupus eritematoso sistémico es el prototipo de las enfermedades autoinmunes no órgano-específicas, con un curso fluctuante entre periodos de remisión y crisis. La complejidad de sus mecanismos fisiopatológicos mantiene la necesidad de desarrollar nuevos tópicos de investigación que faciliten su entendimiento y generen potenciales blancos terapéuticos. La vía de señalización Wnt y su principal inhibidor la protema Dickkopf-1 tienen un rol trascendental en fenómenos biológicos como la homeostasis ósea. Sin embargo, estudios recientes en lupus eritematoso sistémico han permitido reconocer otros procesos extraóseos regulados por la proteína Dickkopf-1. Entre ellos: la preservación de la integridad de las membranas glomerulares a nivel renal, reversión de rasgos de senescencia de células mesenquimales de interés en la optimización de los planes de trasplante como medida terapéutica; y la homeostasis articular. Alrededor de estos resultados han de suscitarse nuevas investigaciones sobre la proteína Dickkopf-1 y lupus eritematoso sistémico, que consoliden la información obtenida dado el gran potencial clínico y terapéutico que implica.
Systemic lupus erythematosus is the prototype of non-organ specific autoimmune diseases, with a fluctuating course between remission and crisis. The complexity of pathophysiological mechanisms opens up the possibility to develop multiple research topics to facilitate their understanding and generate potential therapeutic targets. The Wnt signalling pathway and its main inhibitor, Dickkopf-1 protein, have a major role in biological phenomena, such as bone homeostasis. However, recent studies have enabled other extra-osseous processes regulated by Dickkopf-1 to be recognised. These include: preserving the integrity of kidney glomerular membranes, senescence reversal characteristics of mesenchymal cells of interest in optimising transplantation plans as a therapeutic measure, and joint homeostasis. Some of these results have led to further research into Dickkopf-1 and systemic lupus erythematosus, in order to consolidate the information obtained given the great clinical and therapeutic potential involved.
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Humans , Autoimmune Diseases , Lupus Erythematosus, SystemicABSTRACT
Objective:To investigate the effect of DKK1 on linearly patterned programmed cell necrosis (LPPCN) and vasculogenic mim-icry (VM) and the related molecular mechanism in non-small cell lung cancer (NSCLC). Methods:A total of 173 human NSCLC speci-mens were collected to detect LPPCN by H&E staining, detect VM with CD31/PAS double staining, and investigate DKK1 and related protein expression by immunohistochemistry. The clinical pathological significance of LPPCN, VM, and DKK1 and the correlation of them were analyzed. Human NSCLC H460-DKK1 cells were engrafed in nude mice to evaluate the influence of DKK1 up-regulation on VM and LPPCN in vivo. Results:Approximately, 14.45%(25/173) of NSCLC had VM and 49.71%(86/173) had LPPCN. 25.6%(22/86) of NSCLC cases in LPPCN-positive group formed VM. Both of VM and LPPCN were all correlated with poor differentiation, late TNM stage, easy recurrence and metastasis and poor prognosis in NSCLC. DKK1 expression in the VM-positive group and the LPPCN-positive group was higher than that in the VM-negative group and the LPPCN-negative group, respectively. DKK1, LPPCN, and VM were positive-ly correlated with VE-cadherin, MMP-2,β-catenin nuclear expression and Twist1. H460-DKK1 transplantation tumor model confirmed that DKK1 promotes the expression of VM and LPPCN and related proteins in NSCLC. Conclusion:The increase of theβ-catenin and Twist1 expression induced by DKK1 may promote the formation of LPPCN and VM in NSCLC.
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La artritis reumatoide (AR) es una enfermedad inflamatoria sistémica crónica, caracterizadapor la formación de pannus, destrucción articular, deformidad, discapacidad y disminuciónde la calidad y de la expectativa de vida. La vía de senalización Wnt juega un papel importanteen un sinnúmero de procesos fisiológicos. Desde hace algunos anos ha sido implicadaen la regulación de células fundamentales para la homeostasis del hueso. Estudios recientessugieren que esta vía juega un rol en la patogénesis de la AR, mediante la sobreexpresión deinhibidores de esta vía como la proteína Dickkopf 1 (DKK1), la cual afecta de manera negativala diferenciación y la actividad de los osteoblastos. Niveles elevados de esta proteína sehan asociado a mayor progresión radiológica y a actividad de la enfermedad. Sin embargo,aún no está claro el papel de esta vía y del DKK1 en la AR. Más estudios al respecto podríanayudarnos a comprender las diferencias en la presentación clínica y en el pronóstico de estaenfermedad. Adicionalmente, podrían sugerir nuevos blancos terapéuticos...
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Humans , Arthritis, Rheumatoid , OsteoprotegerinABSTRACT
La arteritis de Takayasu es una vasculopatía crónica inflamatoria e idiopática de las grandesarterias, cuyas consecuencias son cambios oclusivos, estenóticos o aneurismáticos de laaorta y de sus ramas inmediatas.Se presenta el caso de una mujer de 37 anos con déficit neurológico focal y angiorresonancia,que demuestra disminución del flujo de la arteria carótida interna izquierda yadelgazamiento de la arteria cerebral izquierda con aortograma torácico y de vasos de cuelloque confirma los hallazgos y, además, demuestra estenosis de la arteria subclavia izquierda,cumpliendo los criterios clasificatorios de una arteritis de Takayasu.Se realiza una revisión de la arteritis de Takayasu, haciendo énfasis en la fisiopatología,manifestaciones clínicas, diagnóstico, tratamiento y pronóstico...
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Humans , Arteritis , Rheumatology , Takayasu ArteritisABSTRACT
Aim To investigate the alteration of Wnt/β-catenin signaling pathway in early diabetic rat myo-cardium and clarify its role in development of diabetic cardiomyopathy. Methods The diabetes mellitus ( DM) model was prepared by intraperitoneal injection of streptozotocin ( STZ, 60 μg · g-1 ) . The alteration of Wnt/β-catenin signaling pathway was determined by Western blot and immunohistochemistry. HE staining was used to analyze the change of myocardial pathologi-cal structure. Results Cardiac histological analyses revealed that DM induced cardiomyocyte degeneration and necrosis. Myocardial Wnt2, β-catenin and c-Myc were enhanced in 2 wk DM compared with control group while DKK1 showed no significant alteration. Conclusion Wnt/β-catenin signaling pathway is acti-vated in early diabetic myocardial injury. Further re-searches on its role in DM myocardium may find a new therapeutic target for diabetic cardiomyopathy.