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1.
Bioorg Chem ; 112: 104912, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33933804

RESUMEN

Orphan nuclear receptor Nur77 is a unique member of the NR4A nuclear receptor subfamily, which is critical for cellular processes especially the inflammatory responses. Many efforts have been made to discover novel scaffold small molecules targeting Nur77. Herein, we evaluated the previously reported binding sites in crystal structures of Nur77 with small molecules, and then discovered compound 13 as a hit of Nur77 via virtual screening targeting the best-scored binding site. Based on the results of fluorescence titration assay, structure-activity relationship (SAR) analysis was summarized for compound 13 and its analogs. Among these analogs, compound 13e displayed the most potent binding affinity (0.54 ± 0.02 µM). The binding mode of compound 13e was predicted via molecule docking. Moreover, 13e exhibited significant anti-inflammation activity in TNF-α induced HepG2 cell model. Taken together, these results provided a new insight into the understanding the functions of specific binding sites on Nur77 for small molecular compounds, and the development of new scaffold Nur77 modulators.

2.
Cell Death Dis ; 12(5): 454, 2021 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-33963177

RESUMEN

Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

3.
J Hazard Mater ; 416: 125814, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33866290

RESUMEN

Pleurotus has great potential for heavy metal mycoremediation. Using comparative transcriptome analysis, the response of Pleurotus ostreatus and Pleurotus cornucopiae under Cd contamination was evaluated. P. ostreatus and P. cornucopia accumulated 0.34 and 0.46 mg/g Cd in mycelium, respectively. Cd removal elevated with its concentration elevation, which reached 56.47% and 54.60% for P. ostreatus and P. cornucopia with Cd at 20 mg/L. Low-level Cd (≤ 1 mg/L) had no significant influence on either fungus, while varied response was observed under high-level Cd. 705 differentially expressed genes (DEGs) were identified in P. cornucopia at Cd1 and Cd20, whereas 12,551 DEGs in P. ostreatus. Differentially regulated functional categories and pathways were also identified. ATP-binding cassette transporters were involved in Cd transport in P. cornucopia, whereas the endocytosis and phagosome pathways were more enhanced in P. ostreatus. 26 enzymes including peroxisomal enzymes catalase and superoxide dismutase were upregulated in P. ostreatus, whereas only cytosolic catalase was overexpressed in P. cornucopia, suggesting their different Cd detoxification pathways. Also, the mitogen-activated protein kinase signaling pathway involved in Cd resistance in both species instead of glutathione metabolism, although more active in P. ostreatus. These findings provided new insight into the molecular mechanism of mycoremediation and accumulator screening.

4.
J Med Chem ; 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33876637

RESUMEN

Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1, which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.

5.
Bioorg Med Chem Lett ; 41: 127986, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33766770

RESUMEN

Monoacylglycerol lipase (MAGL) is the major enzyme that catalyzes the hydrolysis of monoacylglycerols (MAGs). MAGL is responsible for degrading 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain and specific tissues. The inhibition of MAGL could attenuate the inflammatory response. Here, we report a series of reversible non-covalent MAGL inhibitors via virtual screening combined with biochemical analysis. The hit, DC630-8 showed low-micromolar activity against MAGL in vitro, and exhibited significant anti-inflammatory effects.

6.
Environ Pollut ; 279: 116898, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-33756241

RESUMEN

Assessing the vertical distribution of aerosols in the atmosphere can elucidate the regional sources of accumulated pollutants at different altitudes. Although studies in Hefei have mainly focused on aerosols in the near-surface atmosphere, few studies have assessed the vertical variability in aerosol concentrations. In this study, the vertical aerosol distribution in Hefei was analyzed continuously for one year (from March 2018 to February 2019) using multi-axis differential optical absorption spectroscopy. The aerosol extinction coefficient was the highest in winter (0.94 km-1), followed by autumn (0.63 km-1), spring (0.57 km-1), and summer (0.47 km-1). Local pollution caused the accumulation of aerosols near the surface. The rate of decrease of the aerosol extinction coefficient was higher in autumn and winter than in spring and summer. The diurnal variations of aerosol extinction coefficient in the different seasons were affected by the planetary boundary layer height, and we observed notable high-altitude transport of aerosols in autumn. We assessed the vertical distribution of the aerosol extinction coefficient under different pollution concentrations and identified peak values mainly below a height of 0.5 km. With increasing height, the extinction coefficient decreased linearly and slowly under low PM2.5 concentrations, whereas decreased more rapidly under high PM2.5 concentrations. Clustering analysis, the weight potential source concentration function, and the concentration weighted trajectory model inferred different seasonal characteristics in the potential source areas of aerosols at different heights. In addition to local pollution sources, Jiangsu Province was found to be the main source of pollution in Hefei at a height of 0.4 km, whereas Hubei Province was the main source of pollution at a height of 2 km.


Asunto(s)
Contaminantes Atmosféricos , Ríos , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , China , Monitoreo del Ambiente , Estaciones del Año
7.
Bioresour Technol ; 330: 124965, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33735725

RESUMEN

With the increasing of data in wastewater treatment, data-driven machine learning models are useful for modeling biological processes and complex reactions. However, few data-driven models have been developed for simulating the microbial electrolysis cells (MECs) and traditional models are too ambiguous to comprehend the mechanisms. In this study, a new general data-driven two-stage model was firstly developed to predict CH4 production from in-situ biogas upgrading in the biocathode MECs via direct electron transfer (DET), named NARX-BP hybrid neural networks. Compared with traditional one-stage model, the model could well predict methane production via DET with excellent performance (all R2 and MES of 0.918 and 6.52 × 10-2, respectively) and reveal the mechanisms of biogas upgrading, for the new systematical modeling approach could improve the versatility and applicability by inputting significant intermediate variables. In addition, the model is generally available to support long-term prediction and optimal operation for anaerobic digestion or complex MEC systems.


Asunto(s)
Biocombustibles , Metano , Anaerobiosis , Reactores Biológicos , Electrólisis , Electrones , Aprendizaje Automático , Redes Neurales de la Computación
8.
J Hazard Mater ; 412: 125156, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-33556857

RESUMEN

Microbially induced phosphate precipitation (MIPP) is an advanced bioremediation technology to immobilize heavy metals. An indigenous bacterium QY14 with the function of mineralization isolated from Cd contaminated farmland soil was identified as Burkholderia ambifaria. The minimum inhibitory concentration value for QY14 was 550 mg/L for soluble Cd concentration. This study found that the addition of 10 mM Ca2+ during MIPP process could significantly increase the removal ratio of Cd, and the maximum removal ratio of Cd with 10 mM Ca2+ and without Ca2+ in solution was 99.97% and 76.14%, respectively. The increase of acid phosphatase activity and the formation of precipitate containing calcium caused by 10 mM Ca2+ addition contributed the increase of Cd removal efficiency. The results of SEM-EDS, FTIR and XRD showed that Cd was removed by forming Cd containing hydroxyapatite (Cd-HAP). In addition, the dissolution experiment showed the Cd release ratio of Cd-HAP (0.01‰ at initial pH 3.0 of solution) was lower than Cd-absorbed HAP, indicating that Cd was more likely removed by the formation of Ca10-xCdx(PO4)6(OH)2 solid solution. Our findings revealed MIPP-based bioremediation supplied with 10 mM Ca2+ could increase the Cd removal and could potentially be applied for Cd remediation.

9.
Gut ; 2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33632712

RESUMEN

OBJECTIVE: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells. CONCLUSION: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

10.
Ann Plast Surg ; 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33587459

RESUMEN

BACKGROUND: Dynamic infrared thermography provides a new imaging method of perforator detection. This study introduces an augmented technique to improve its accuracy by tourniquet-reperfusion and reports its preliminary use in the distal lower leg reconstruction. METHODS: A tourniquet (450 mm Hg) was applied for 3 minutes on proximal thighs. After the tourniquet release, the rewarming rate and pattern of hotspots were observed by thermography to delineate the location and quality of perforators. The results were compared with those detected by computed tomographic angiography. Clinically, the local transferred posterior tibial artery or peroneal artery propeller perforator flap was performed in 9 patients for the distal lower leg reconstruction. RESULTS: There was a 20- to 140-second "perforator observing window" after the tourniquet release. Tourniquet-reperfusion augmented thermal imaging method (TRATIM) had a sensitivity of 90.3% and a positive predictive value of 93.3%. The TRATIM and computed tomographic angiography had an excellent concordance with a kappa index value of 0.839 (P < 0.001). Based on the TRATIM, 9 propeller perforator flaps were successfully designed and raised for the distal lower leg resurfacing. All flaps survived entirely, except one with size of 1.0 cm × 2.0 cm that had terminal necrosis. CONCLUSIONS: The TRATIM is a quick, easy, cheap, and reliable approach for perforator detection in the lower leg. With the aid of TRATIM, a customized propeller perforator flap could be raised efficiently for the distal lower leg reconstruction.

11.
Signal Transduct Target Ther ; 6(1): 26, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33473101

RESUMEN

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3-14 doses/person). In total, 12-30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1-2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

12.
Oxid Med Cell Longev ; 2021: 3756925, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33510836

RESUMEN

Fas-associated factor 1 (FAF1), a member of the Fas death-inducing signaling complex, is reported to interact potentially with diverse proteins and function in diverse cellular possesses. It remains unclear, however, whether FAF1 is involved in hepatic metabolic disorder and insulin resistance. This study is aimed at elucidating the role and the molecular mechanism of FAF1 in hepatic insulin resistance. Rats treated with high-fat diets are used as hepatic insulin resistance animal models. Quantitative real-time PCR, immunohistochemistry, and immunofluorescence assay are utilized to detect the FAF1 expression. The expression of relevant proteins is detected by Western blotting. We determine ROS production, lipid accumulation, and glucose uptake by using flow cytometry. Immunoprecipitation is employed to investigate protein-protein interaction. We find that increased expression of FAF1 occurred in the livers of insulin-resistant rats. Using gain-of-function and loss-of-function approaches, we observe dramatic exacerbation of insulin resistance, upregulated gluconeogenesis genes, downregulated glucose transport genes, and enhanced ROS production by FAF1 overexpression, whereas downregulation of FAF1 leads to a completely opposite phenotype. Mechanistically, FAF1 interacts directly with c-Jun N-terminal kinase (JNK) and activates its phosphorylation, thereby blocking the downstream insulin signaling pathway and leading to insulin resistance. Our data indicate that FAF1 is a potent regulator in hepatic metabolic disorder and insulin resistance.

13.
J Clin Endocrinol Metab ; 106(4): 988-998, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33428730

RESUMEN

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients. METHODS: Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated. RESULTS: The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways. CONCLUSIONS: This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.

14.
Ecotoxicol Environ Saf ; 211: 111929, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33472107

RESUMEN

Large amounts of cadmium (Cd) have been discharged into soil with the rapid development of industry. In this study, we revealed the impacts of Coprinus comatus (C. comatus) and Pleurotus cornucopiae (P. cornucopiae) on soil and the tolerance responses of macrofungi in the presence of Cd by the analysis of soil biochemical properties and macrofungi growth indexes. Results showed that with the cultivation of C. comatus and P. cornucopiae, the HOAc-extractable Cd in soil individually reduced by 9.53% and 11.35%, the activities of soil urease, acid phosphatase, dehydrogenase, and Fluorescein diacetate (FDA) hydrolysis increased by 18.11-101.45%, 8.39-18.24%, 9.37-55.50% and 28.94-41.92%, respectively. Meanwhile, different soil bacterial communities were observed with various macrofungi cultivations. Also, Cd accumulation significantly enhanced the macrofungi antioxidant enzyme activities, which increased by 24.10-45.43%, 30.11-61.53% and 7.03-26.81% for catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) activities in the macrofungi, respectively. Moreover, the enhanced macrofungi endophytic bacterial diversities with Cd existence was firstly observed in the present experiment. These findings revealed the possible Cd resistance mechanisms in macrofungi, suggesting C. comatus and P. cornucopiae were promising ameliorators for Cd contaminated soil.


Asunto(s)
Adaptación Fisiológica , Biodegradación Ambiental , Cadmio/toxicidad , Coprinus/fisiología , Pleurotus/fisiología , Contaminantes del Suelo/toxicidad , Antioxidantes/análisis , Bacterias , Cadmio/análisis , Catalasa , Suelo/química , Contaminantes del Suelo/análisis
15.
Cell Death Dis ; 12(1): 69, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33431817

RESUMEN

Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients' survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT-DNA-PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN-ATM-CHK2 signal and ATR-CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.

16.
Bioorg Med Chem ; 29: 115890, 2020 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-33285407

RESUMEN

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.

17.
Contemp Clin Trials ; : 106215, 2020 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-33217555

RESUMEN

It is well known that if the hypothesis test is left unchanged, the Type I error rate may be inflated for sample size re-estimation (SSR) designs. To address this issue, three main approaches have been proposed in the literature: combination test, conditional error and conventional test with sample size increase in the allowable region (AR) only. These three seemingly different approaches are in fact connected. For each combination test, there is a corresponding conditional error function and AR. Designing adaptation rules in this AR with conventional test guarantees the Type I error rate control but at the same time always leads to smaller power comparing to the corresponding combination test (or conditional error) approach. In cases where conventional test is still preferable, step-wise adaptation rules as proposed in Liu and Hu (Liu and Hu, 2015 [46]) can be alternatively considered. This type of adaptation rule does not need to be fully contained in the AR for Type I error rate control, thus may not necessarily be less powerful. We believe controversies in the statistical community on the efficiency comparisons between group sequential (GS) and SSR design stem partially from the misalignment of performance metrics and conditional versus unconditional interpretations. We advocate summary metrics, such as median, variance or tail probabilities of the sample size in addition to expectation and that the definition of efficiency be tailored to individual sponsor. Conditional metrics by favorable, promising and unfavorable zones of the interim results provide additional insights and should always be incorporated into the decision process.

19.
Burns Trauma ; 8: tkaa025, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33150188

RESUMEN

Background: Keloid is a fibrotic dermal disease characterized by an abnormal increase in fibroblast proliferation and invasion. These pathological behaviours may be related to the heterogeneity of keloid fibroblasts (KFs); however, because of a lack of effective biomarkers for KFs it is difficult to study the underlying mechanism. Our previous studies revealed that the expansion of CD26+ KFs was responsible for increased keloid proliferation and invasion capabilities; the intrinsic relationship and mechanism between CD26 and keloid is therefore worthy of further investigation. The aim of this study was to explore molecular mechanisms in the process of CD26 upregulated KFs proliferation and invasion abilities, and provide more evidence for CD26 as an effective biomarker of keloid and a new clinical therapeutic target. Methods: Flow cytometry was performed to isolate CD26+/CD26- fibroblasts from KFs and normal fibroblasts. To generate stably silenced KFs for CD26 and insulin-like growth factor-1 receptor (IGF-1R), lentiviral particles encoding shRNA targeting CD26 and IGF-1R were used for transfection. Cell proliferations were analysed by cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Scratching assay and transwell assay were used to assess cell migration and invasion abilities. To further quantify the regulatory role of CD26 expression in the relevant signalling pathway, RT-qPCR, western blot, ELISA, PI3K activity assay and immunofluorescence were used. Results: Aberrant expression of CD26 in KFs was proven to be associated with increased proliferation and invasion of KFs. Furthermore, the role of the IGF-1/IGF-1 receptor axis was also studied in CD26 and was found to upregulate KF proliferation and invasion. The PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway was shown to affect CD26-regulated KF proliferation and invasion by increasing phosphorylation levels of S6 kinase and 4E-binding protein. Conclusions: CD26 can be the effective biomarker for KFs, and its expression is closely related to proliferation and invasion in keloids through the IGF-1-induced PI3K/AKT/mTOR pathway. This work provides a novel perspective on the pathological mechanisms affecting KFs and therapeutic strategies against keloids.

20.
Onco Targets Ther ; 13: 9407-9417, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33061427

RESUMEN

Objective: The aim of this study was to estimate the relevance of the epidermal growth factor receptor (EGFR) between serum vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) in primary hepatocellular carcinoma (HCC) patients with transarterial chemoembolization (TACE). Methods: The pre-treatment and post-treatment concentrations of the serum VEGF and MMP­9 were detected with Luminex assay in 80 EGFR-negative patients and 59 EGFR-positive patients who received TACE therapy with different chemotherapeutic drugs. Results: The serum concentration of MMP-9 in the EGFR-positive patients with primary HCC was significantly higher than that in the EGFR-negative patients (P < 0.05). In EGFR-positive patients with primary HCC, differences in stage, metastasis, and differentiation were significant (P < 0.05). Serum VEGF level significantly decreased at the second course of treatment in the EGFR-negative patients from the P group (P < 0.05), while serum MMP-9 level significantly decreased at the second course of treatment in the EGFR-negative patients from the E group (P < 0.05). Serum VEGF level in the EGFR-positive patients among three groups slightly decreased at the first, second and third courses of treatments; however, the differences were not significant (P > 0.05). Serum MMP-9 level in the EGFR-positive patients among three groups showed mild decrease at the first and second courses of treatments; however, the decreases at the third course of treatment were significant (P < 0.05). Conclusion: Serum VEGF and MMP-9 are potential biomarkers for the treatment monitoring of EGFR-positive and -negative patients after TACE therapy with different chemotherapeutic drugs.

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