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1.
Mol Ther ; 31(2): 503-516, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36384875

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Gencitabina , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Desoxicitidina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Transdução de Sinais , Resistencia a Medicamentos Antineoplásicos/genética
2.
Zhongguo Zhong Yao Za Zhi ; 46(22): 5804-5809, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34951168

RESUMO

Whitmania pigra is the most widely distributed species of leeches in the market. In this study, the effect of heavy metal lead pollution on the anticoagulant activity of Wh. pigra was studied and the potential mechanism was explored. Pb(NO_3)_2 was used to contaminate the breeding soil which was then used to rear Wh. pigra for 50 days(lead-contaminated group, LC group), and meanwhile the blank control group(CG group) was set. Proteins were extracted from the obtained leech samples, and the differentially expressed proteins between LC and CG groups were analyzed by label-free proteomics technology. In this study, a total of 152 differentially expressed proteins were screened out, of which 93 proteins were up-regulated and 59 proteins were down-regulated in LC group. Bioinformatics analysis showed that the biological processes enriched with the differentially expressed proteins were mainly vesicle-mediated transport and transport positive regulation; the enriched cell components were mainly endocytosis vesicles and apical plasma membrane; the enriched molecular functions mainly included carbohydrate binding. The differentially expressed proteins were enriched in 76 KEGG pathways, which mainly involved metabolic pathways, biosynthesis of secondary metabolites, and bacterial invasion of epithelial cells. In this study, two differentially expressed proteins with Antistasin domain were presumed, which provides reference for further exploring the regulatory mechanism and signal transduction underlying the effect of lead pollution on the anticoagulant activity of leech.


Assuntos
Sanguessugas , Metais Pesados , Animais , Anticoagulantes/farmacologia , Poluição Ambiental , Proteômica
3.
BMC Infect Dis ; 20(1): 856, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203355

RESUMO

BACKGROUND: Disseminated Nocardia infection is a disease that is easily overlooked in patients with lesions occupying the intracranial space complicated with coma. Early diagnosis and treatment are crucial. CASE PRESENTATION: A 65-year-old man was admitted to the First Affiliated Hospital of Zhejiang University in October 2018 with weakness in the right limbs for 3 days and altered consciousness for 1 day. Five months earlier, he had been diagnosed with membranous kidney disease and had received cyclophosphamide and prednisone. At admission, the white blood cell count was 1.37 × 1010/L (with 86.4% neutrophils), and C-reactive protein was 115.60 mg/L. Imaging examinations revealed a lesion occupying the intracranial space, lung infection, and multiple abscesses in the rhomboid muscle. The abscesses were drained. Pus culture confirmed Nocardia cyriacigeorgica infection. With antibiotics and vacuum-sealed drainage of the back wound, the patient improved and was discharged from the hospital. CONCLUSIONS: This case report shows that infection should be considered during the differential diagnosis of lesions in the intracranial space, especially in patients receiving immunosuppressive treatment. In patients with disseminated N. cyriacigeorgica infection, combination antibiotic therapy and surgical drainage of localised abscesses can be effective.


Assuntos
Coma/complicações , Mesencéfalo/diagnóstico por imagem , Nocardiose/complicações , Nocardiose/diagnóstico , Nocardia/isolamento & purificação , Tálamo/diagnóstico por imagem , Idoso , Antibacterianos/uso terapêutico , Ciclofosfamida/efeitos adversos , Diagnóstico Diferencial , Drenagem , Seguimentos , Humanos , Imunossupressores/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/patologia , Nocardiose/tratamento farmacológico , Nocardiose/microbiologia , Tálamo/patologia , Tomógrafos Computadorizados , Resultado do Tratamento
4.
Cancer Sci ; 110(10): 3110-3121, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385398

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fourth leading cause of cancer-related death worldwide. Our previous study showed that EYA4 functioned by suppressing growth of HCC tumor cells, but its molecular mechanism is still not elucidated. Based on the results of gene microassay, EYA4 was inversely correlated with MYCBP and was verified in human HCC tissues by immunohistochemistry and western blot. Overexpressed and KO EYA4 in human HCC cell lines confirmed the negative correlation between EYA4 and MYCBP by qRT-PCR and western blot. Transfected siRNA of MYCBP in EYA4 overexpressed cells and overexpressed MYCBP in EYA4 KO cells could efficiently rescue the proliferation and G2/M arrest effects of EYA4 on HCC cells. Mechanistically, armed with serine/threonine-specific protein phosphatase activity, EYA4 reduced nuclear translocation of ß-catenin by dephosphorylating ß-catenin at Ser552, thereby suppressing the transcription of MYCBP which was induced by ß-catenin/LEF1 binding to the promoter of MYCBP. Clinically, HCC patients with highly expressed EYA4 and poorly expressed MYCBP had significantly longer disease-free survival and overall survival than HCC patients with poorly expressed EYA4 and highly expressed MYCBP. In conclusion, EYA4 suppressed HCC tumor cell growth by repressing MYCBP by dephosphorylating ß-catenin S552. EYA4 combined with MYCBP could be potential prognostic biomarkers in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/genética , Neoplasias Hepáticas/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , beta Catenina/metabolismo , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Serina/metabolismo , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Transcrição Gênica , beta Catenina/química
5.
Gynecol Endocrinol ; 35(9): 825-828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30990090

RESUMO

The aim of this study is to review the natural course, clinical features, and reproductive prognosis of ovarian tumors associated with hyperandrogenemia. We retrospect 33 patients of ovarian tumors with hyperandrogenemia. Thirty cases (91%) were sex cord-stromal tumors. Sertoli-Leydig cell tumors, Leydig cell tumors, and steroid cell tumors were the most common types. It is not possible, to predict the pathological subtypes based on androgen levels alone. Most of these tumors were solid masses, with an average diameter of 3.9 cm. These tumors are soft or fragile, no clear boundary with normal tissue, thus excision is superior to exfoliation. The average disease course of the top three tumors was 32.6, 35.4, and 67.7 months, respectively. Among 11 married women with a desire to get pregnant, nine cases resumed menstrual periods after surgery and became pregnant naturally. Hyperandrogenemia might predict a better prognosis. The asynchronism of hyperandrogenemia and undetectable tumor may cause irreversible change and emotional depress, the methods of early diagnosis need further study.


Assuntos
Hiperandrogenismo/complicações , Hiperandrogenismo/diagnóstico , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Adolescente , Adulto , Idoso , Androgênios/sangue , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Preservação da Fertilidade , Humanos , Hiperandrogenismo/patologia , Hiperandrogenismo/cirurgia , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Prognóstico , Estudos Retrospectivos , Tumor de Células de Sertoli-Leydig/complicações , Tumor de Células de Sertoli-Leydig/diagnóstico , Tumor de Células de Sertoli-Leydig/patologia , Tumor de Células de Sertoli-Leydig/cirurgia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , Carga Tumoral , Adulto Jovem
6.
Zhongguo Zhong Yao Za Zhi ; 44(20): 4433-4438, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872629

RESUMO

Traditional Chinese medicines( TCMs) are easily contaminated by fungi during planting,harvesting,processing,transportation and storage. The 2015 version of Chinese Pharmacopoeia stipulates the detection of aflatoxin in Dilong. After reviewing the literature,it has been found that there are no domestic and foreign scholars who have studied the surface fungi of Dilong. Pheretima,known as Dilong in China,is a commonly used TCMs in animal. In this experiment,8 batches of Dilong were collected from retail pharmacies in Beijing. The fungi on the surface of Dilong were cultured by traditional plate method and the single strain was obtained by the top purification method. The fungal colony morphology,microstructure characteristics and DNA barcode were used to isolate and identify the fungi. At the same time,based on Illumina Hi Seq 2500 high-throughput sequencing platform,the diversity of fungi on the surface of Dilong was analyzed. The results showed that 287 strains of 9 species of fungi were isolated and identified by plate method. Combined with 3 kinds of identification method,eight of nine fungi could be identified,respectively,Aspergillus niger,Penicillium,Alternaria nees,A. flavus,and Penicillium oxalicum,Humicola sp.,Talaromyces purpurogenus and A. insuetus,1 kind of fungi was not identified yet. Among them,Penicillium and Aspergillus were the dominant genus. The results of high-throughput sequencing belonged to 2 boundaries,6 gates,19 classes,44 orders,98 families,127 genus and 121 species in different classification levels. Wallemia,Aspergillus and Cordyceps were the dominant genus,and the relative abundances are 63. 33%,15. 28%,and 10. 28%,respectively. Through the diversity study on the surface fungi of Dilong in Beijing retail pharmacies,it can provide a reference for its safe storage and clinical use.


Assuntos
Aflatoxinas , Medicamentos de Ervas Chinesas , Fungos , Alternaria , Animais , Aspergillus , China , Penicillium
7.
Zhongguo Zhong Yao Za Zhi ; 44(23): 5114-5117, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-32237346

RESUMO

Leech has a good anticoagulant activity and is one of the raw materials for treatment of many cardiovascular and cerebrovascular diseases. This study was based on in vitro anticoagulant experiments( APTT and PT) to investigate the effects of lead contamination on the anticoagulant effect of leech. At present,the Hirudo circulating in the market are dominated by Whitmania pigra,therefore Wh. pigra were cultivated under a different lead pollution for 50 days. Then,the effects of Wh. pigra extract,extracting from different cultivating environment,on activated partial thrombin time( APTT) and prothrombin time( PT) were determined by automatic coagulation instrument. The results showed that the Wh. pigra extract significantly prolonged the APTT compared with the saline group.The APTT of the lead-high residual Wh. pigra was shorter than that of the blank Wh. pigra. The Wh. pigra extracts from different treatment groups had little effect on PT. The results showed that the lead residue in the Wh. pigra increased with the increase of lead in the cultured soil,the lead residual of the Pb-H group was( 10. 66±2. 79) mg·kg~(-1),which exceeded the lead limit specified in the 2015 edition of the Chinese Pharmacopoeia. The results indicated that growth environment pollution is one of the important factors causing excessive lead in Wh. pigra. Lead pollution will reduce the anticoagulant effect of Wh. pigra and affect its clinical efficacy.


Assuntos
Produtos Biológicos/farmacologia , Coagulação Sanguínea , Chumbo/toxicidade , Sanguessugas/efeitos dos fármacos , Animais , Anticoagulantes , Poluição Ambiental , Tempo de Protrombina , Tempo de Trombina
8.
Eur Arch Otorhinolaryngol ; 271(10): 2737-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24728231

RESUMO

The objective of the study was to investigate the relationship between lingua-epiglottis position and glossopharyngeal obstruction in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). One hundred and four patients with OSAHS diagnosed by polysomnography (PSG) were enrolled. Lingua-epiglottis position was visualized using endoscopy and classified into three types. Spiral CT imaging of the upper respiratory tract was performed to measure the cross-sectional area and inner diameter of the glossopharyngeal airway. The PSG was repeated after nasopharyngeal tube insertion (NPT-PSG). The NPT-PSG results, CT-measured data and incidence of stenosis were compared among the different lingua-epiglottis position groups. Obstructive sleep apnea hypopnea syndrome patients with different lingua-epiglottis positions had similar demographics. As lingua-epiglottis position type varied from type I to type III, cross-sectional area and inner diameter of the glossopharyngeal area decreased, glossopharyngeal airway stenosis rate increased, and apnea hypopnea index measured by NPT-PSG increased. The lowest oxygen saturation decreased. Lingua-epiglottis position was significantly related to glossopharyngeal obstruction. Lingua-epiglottis position should be used in clinical practice for the preliminary assessment of glossopharyngeal obstruction.


Assuntos
Epiglote/patologia , Apneia Obstrutiva do Sono/diagnóstico , Língua/patologia , Adulto , Endoscopia , Epiglote/diagnóstico por imagem , Feminino , Humanos , Masculino , Polissonografia/métodos , Estudos Retrospectivos , Apneia Obstrutiva do Sono/etiologia , Apneia Obstrutiva do Sono/fisiopatologia , Tomografia Computadorizada Espiral , Língua/diagnóstico por imagem
9.
Huan Jing Ke Xue ; 45(2): 1058-1068, 2024 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-38471943

RESUMO

In order to explore the characteristics and sources of heavy metal pollution in cultivated soil around a red mud yard in Chongqing, the content and spatial distribution characteristics of eight heavy metal elements (Cd, Cr, Hg, Ni, Pb, As, Cu, and Zn) in the soil were analyzed, and the single factor pollution index method and Nemerow comprehensive pollution index method were used to evaluate the characteristics of heavy metal pollution in soil. On the basis of correlation analysis, the APCS-MLR and PMF models were used to quantitatively analyze the sources of heavy metals. The results showed that the average contents of the other seven heavy metal elements were higher than the background values of Chongqing soil, except for that of Cr. The heavy metals Cd, Hg, and As were moderately polluted, and Pb, Cu, Ni, and Zn were mildly polluted. The spatial distribution pattern of Cr, Ni, Pb, Cu, and Zn in the soil was similar, and there was a very significant positive correlation between them (P < 0.01). The spatial distribution characteristics of Cd, Hg, and As were significantly different, and there was no significant correlation between them (P > 0.05). The source apportionment showed that the sources of heavy metals in the soil in the study area were relatively complex, and the APCS-MLR and PMF models could identify the same four pollution sources, namely red mud yard percolation emission and natural sources, thermal power generation emission sources, agricultural activities and natural sources, and non-ferrous metal smelting emission sources. There was little difference in the results of source apportionment between the two models. The contribution rates of the four pollution sources in the APCS-MLR model were 51.8%, 18.0%, 15.9%, and 14.3%, respectively, whereas those in the PMF model were 45.9%, 12.8%, 21.5%, and 19.8%, respectively.

10.
Huan Jing Ke Xue ; 45(3): 1428-1438, 2024 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-38471858

RESUMO

To understand the water pollution status and environmental risks of Changshou Lake, the concentrations of heavy metals (Cr, Cu, Zn, As, Cd, and Pb) in the water were collected and analyzed during different seasons. The study investigated temporal and spatial variations, distribution characteristics, pollution levels, and health risks associated with heavy metals in Changshou Lake. The results showed that all six heavy metals were below than the Class Ⅰ standard of the Surface Water Environmental Quality Standard (GB 3838-2002), but recent years have witnessed an increasing trend, with Cu, As, and Pb showing a significant increase (P<0.05). The temporal and spatial distributions of these heavy metals were different. Temporally, Cr and Cd concentrations in surface water were higher in summer, As and Zn were higher in spring, and Pb and Cu were higher in autumn and winter. Spatially, the concentrations of Cr, As, Cu, Zn, and Pb showed higher concentrations in the southern outlet of the reservoir, the northwestern Longxi River inlet, and the central part of the reservoir, whereas Cd was higher in the northern stagnant area. The overall levels of heavy metals in the water body of Changshou Lake were low, with Cr and Cu slightly polluted, while other heavy metals were identified as having an insignificant pollution level. Drinking water was the primary exposure pathway to carcinogenic and non-carcinogenic heavy metals in surface water bodies. The health risk values of Cr and As in water bodies were high, ranging from 6.2×10-10 to 3.0×10-4 and 5.1×10-8 to 3.9×10-5, respectively. The corresponding contribution rates for children and adults to the total health risk were high, with Cr accounting for 87.18% and 87.20%, respectively, while As accounted for 12.73% and 12.71%, respectively. Therefore, it is crucial to prioritize environmental risks associated with Cr and Cu, as well as the health risks associated with Cr and As in Changshou Lake These findings provide a scientific foundation for water pollution control and environmental quality improvement in Changshou Lake, and rational development and utilization of water resources.


Assuntos
Água Potável , Metais Pesados , Poluentes Químicos da Água , Cádmio , China , Monitoramento Ambiental , Sedimentos Geológicos , Lagos/análise , Chumbo , Metais Pesados/análise , Medição de Risco , Poluentes Químicos da Água/análise , Humanos , Criança , Adulto
11.
Oncogene ; 43(31): 2405-2420, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38914663

RESUMO

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.


Assuntos
Adenosina , Carcinoma Ductal Pancreático , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Metabolismo dos Lipídeos , Neoplasias Pancreáticas , Fator de Crescimento Transformador beta2 , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Camundongos , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/efeitos dos fármacos , Reprogramação Metabólica , Proteína de Ligação a Elemento Regulador de Esterol 1
12.
Adv Sci (Weinh) ; : e2407069, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39225567

RESUMO

Lipid metabolism reprogramming stands as a fundamental hallmark of cancer cells. Unraveling the core regulators of lipid biosynthesis holds the potential to find promising therapeutic targets in pancreatic ductal adenocarcinoma (PDAC). Here, it is demonstrated that platelet-derived growth factor C (PDGFC) orchestrated lipid metabolism, thereby facilitated the malignant progression of PDAC. Expression of PDGFC is upregulated in PDAC cohorts and is corelated with a poor prognosis. Aberrantly high expression of PDGFC promoted proliferation and metastasis of PDAC both in vitro and in vivo. Mechanistically, PDGFC accelerated the malignant progression of PDAC by upregulating fatty acid accumulation through sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in lipid metabolism. Remarkably, Betulin, an inhibitor of SREBP1, demonstrated the capability to inhibit proliferation and metastasis of PDAC cell lines, along with attenuating the process of liver metastasis in vivo. Overall, the study underscores the pivotal role of PDGFC-mediated lipid metabolism in PDAC progression, suggesting PDGFC as a potential biomarker for PDAC metastasis. Targeting PDGFC-induced lipid metabolism emerges as a promising therapeutic strategy for metastatic PDAC, with the potential to improve clinical outcomes.

13.
Cancer Lett ; 585: 216640, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38290659

RESUMO

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Gencitabina , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Autofagia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética
14.
Ann Transl Med ; 10(2): 78, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35282045

RESUMO

Background: After peripheral nerve injury, Schwann cells proliferate and migrate to the injured site, thereby promoting peripheral nerve regeneration. The process is regulated by various factors. Endothelial cells participate in the process via angiogenesis. However, the effects of endothelial cells on Schwann cells are not yet known. The present study sought to evaluate whether endothelial cells accelerate Schwann cell proliferation and migration. Methods: We established a co-culture model of rat Schwann cells (RSC96s) and rat aortic endothelial cells (RAOECs), and studied the effects of endothelial cells on Schwann cells by evaluating changes in Schwann cell proliferation and migration and related multiple genes and their protein expressions in the co-culture model. Results: The results showed that increasing the proportion of endothelial cells in the co-culture model enhanced the proliferation. At days 1 and 3 following the co-culturing, the relative growth rates of the co-cultured cells were 122.87% and 127.37%, respectively, which showed a significant increase in the viability compared to that of the RSC96s (P<0.05). In this process, the expression of Ki67 increased. The migration ability of Schwann cells was also enhanced. The migration capacity of Schwann cells was detected by wound-healing and Transwell assays. The results of the group with 15% of endothelial cells was significantly higher than the results of the other groups (P<0.0001 and P<0.05, respectively). Further, neuregulin 1 and glial fibrillary acidic protein increased the process of Schwann cell migration. Conclusions: The results showed that endothelial cells can promote the proliferation and migration of Schwann cells and participate in peripheral nerve regeneration.

15.
Int J Gen Med ; 14: 8389-8397, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34819747

RESUMO

OBJECTIVE: The majority of giant cell tumors of bone (GCTB) occur in adult patients, especially between the ages of 20 and 40. This study aims to investigate the imaging features of GCTBs in pediatric patients and compare their characteristics with adult cases. METHODS: Fifty-seven cases of patients aged 18 years old or younger were retrospectively analyzed, accounting for 12.8% of GCTBs in the First Affiliated Hospital of Zhengzhou University from 2001 to 2019. One hundred twenty-six adult patients (19 years of age and older) with GCTB occurring in long tubular bones were also included in this study. The following clinical information was identified from the medical records: age, sex, and follow-up data. Imaging features were reviewed by two musculoskeletal radiologists. Patient characteristics and imaging features between the two groups were compared. RESULTS: A total of 57 patients (32 females, 25 males) were included in the study. The patients' ages ranged from 9 to 18 (median = 17 y). The majority of tumors occurred in tubular bones (n = 38, 66.7%) and the pelvis (n = 8, 14.0%). Imaging features were identified in GCTB cases occurring in the long tubular bones. Compared with adult GCTB patients, pediatric GCTB patients had a larger superior-inferior (SI) diameter (P = 0.005) and smaller left-to-right diameter/SI diameter ratio (P = 0.001). Epiphyseal involvement was relatively less common in pediatric patients with GCTBs than in adult patients (P = 0.009). The median age of patients without epiphyseal involvement was lower than the median age of patients with epiphyseal involvement (11 vs 17 y). CONCLUSION: GCTB in the pediatric age group is rare. This study has found that, in pediatric patients with GCTBs, the epiphysis is relatively less involved, and the tumor is more likely to grow longitudinally. These findings are helpful in the diagnosis of GCTBs in the pediatric population.

16.
Nanoscale ; 12(29): 15767-15774, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32729861

RESUMO

Survival data have shown little therapeutic improvement in pancreatic ductal adenocarcinoma (PDAC) over the past several decades, mostly due to aggressive growth and resistance to therapy. Glutathione (GSH) depletion in PDAC may serve as a strategy to suppress tumour malignancy and sensitize tumour cells to therapy. Herein, novel l-cysteine-based poly(disulfide amide) polymers were fabricated to deliver a histone methyltransferase G9a inhibitor (UNC0638) that can simultaneously block GSH biosynthesis and clear cellular GSH levels in PDAC. The optimal UNC0638 nanodrug (NPUNC0638) had the desired particle size, reasonable drug loading capacity, and GSH-controlled drug release. Moreover, compared to UNC0638 alone, NPUNC0638 showed better efficacy in inhibiting cell viability, arresting the cell cycle, inducing apoptosis, and suppressing the invasion and self-renewal capacity of PDAC cells. Furthermore, NPUNC0638 was found to be tumour-specific and well tolerated with no apparent toxicity to vital organs and haematopoietic stem and progenitor cells. Additionally, treatment with NPUNC0638 provided favourable outcomes in the PDAC xenograft model. Therefore, this work presents a potent drug delivery platform to overcome the GSH-induced malignant potential of PDAC.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Preparações Farmacêuticas , Linhagem Celular Tumoral , Histona Metiltransferases , Histonas , Humanos , Oxirredução , Neoplasias Pancreáticas/tratamento farmacológico
17.
Adv Sci (Weinh) ; 7(7): 1902926, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32274304

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant cancer with complex genomic variations, and no targetable genomic lesions have been found yet. Super-enhancers (SEs) have been found to contribute to the continuous and robust oncogenic transcription. Here, histone H3 lysine 27 acetylation (H3K27ac) is profiled in PDAC cell lines to establish SE landscapes. Concurrently, it is also shown that PDAC is vulnerable to the perturbation of the SE complex using bromodomain-containing protein 4 (BRD4) inhibitor, JQ1, synergized with cyclin-dependent kinase 7 (CDK7) inhibitor, THZ1. Formulations of hydrophobic l-phenylalanine-poly (ester amide) nanoparticles (NPs) with high drug loading of JQ1 and THZ1 (J/T@8P4s) are further designed and developed. J/T@8P4s is assessed for size, encapsulation efficiency, morphology, drug release profiles, and drug uptake in vitro. Compared to conventional free drug formulation, the nanodelivery system dramatically reduces the hepatotoxicity while significantly enhancing the tumor inhibition effects and the bioavailability of incorporated JQ1 and THZ1 at equal doses in a Gemcitabine-resistant PDAC patient-derived xenograft (PDX) model. Overall, the present study demonstrates that the J/T@8P4s can be a promising therapeutic treatment against the PDAC via suppression of SE-associated oncogenic transcription, and provides a strategy utilizing NPs to assist the drug delivery targeting SEs.

18.
Int J Biol Sci ; 16(7): 1207-1217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174795

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy with high mortality and lack of effective therapeutic targets. Here, we found that expression of cyclin-dependent kinase 7 (CDK7) was significantly associated with higher tumor grade and worse prognosis in 96 ICC specimens. Depletion of CDK7 significantly inhibited cell growth, induced a G2/M cell cycle arrest, and reduced the migratory and invasive potential in ICC cells. Subsequent experiments demonstrated that ICC cells were highly sensitive to the CDK7 inhibitor THZ1. A low concentration of THZ1 markedly inhibited cell growth, cell cycle, migration, and invasion in ICC cell lines. RNA-sequencing (RNA-seq) analysis revealed that THZ1 treatment decreased the levels of massive oncogene transcripts, particularly those associated with cell cycle and cell migration. Quantitative reverse transcriptase PCR (qRT-PCR) analysis confirmed that transcription of oncogenes involved in cell cycle regulation (AURKA, AURKB, CDC25B, CDK1, CCNA2, and MKI67) and the c-Met pathway (c-Met, AKT1, PTK2, CRK, PDPK1, and ARF6) was selectively repressed by THZ1. In addition, THZ1 exhibited significant anti-tumor activity in a patient-derived xenograft (PDX) model of ICC, without causing detectable side effects.


Assuntos
Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Quinases Ciclina-Dependentes/metabolismo , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Colangiocarcinoma/genética , Quinases Ciclina-Dependentes/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Quinase Ativadora de Quinase Dependente de Ciclina
19.
Asian J Surg ; 32(2): 89-94, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19423455

RESUMO

OBJECTIVE: To study the effect of low molecular weight heparin (LMWH) in the treatment of severe acute pancreatitis (SAP). METHODS: A total of 265 SAP patients were randomly divided into two groups: firstly, the conventional treatment group (C group, n = 130; and secondly the conventional treatment plus the LMWH treatment group (LT group, n = 135). The clinical parameters, laboratory parameters and computed tomography (CT) score of pancreatic necrosis (CTSPN) in the two groups were compared. RESULTS: On admission, all the clinical parameters, laboratory parameters and CTSPN in the two groups were not significantly different (p > 0.05). However, after treatment, in LT group, the clinical presentation improvement rate and laboratory parameters improvement were significantly higher than those in C group (p < 0.05-0.01), and the acute physiology and chronic health evaluation (APACHE) II score, complication rate, mortality and mean hospital stay in LT group were obviously lower than those in C group (p < 0.05-0.01). The CT score in LT group was much lower than that in C group (p < 0.05). Two weeks after treatment FBI decreased obviously in C group, but not in LT group, and no haemorrhagic complications occurred. CONCLUSIONS: LMWH can enhance the effect of conventional treatment for SAP, and can markedly decrease the mortality of SAP. LMWH is a simple, safe, economic and effective method for treatment of SAP. It is can be used in every hospital.


Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Pancreatite/tratamento farmacológico , APACHE , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/epidemiologia , Estudos Prospectivos , Adulto Jovem
20.
Journal of Clinical Hepatology ; (12): 1493-1497, 2024.
Artigo em Chinês | WPRIM | ID: wpr-1038669

RESUMO

Ferroptosis suppressor protein 1 (FSP1) is another major ferroptosis regulator besides glutathione peroxidase 4, which can scavenge intracellular reactive oxygen species and lipid peroxides and inhibit ferroptosis. In view of the key role of the liver in iron and lipid metabolism and its susceptibility to oxidative damage, more and more evidence has shown that FSP1 plays an important role in liver diseases such as metabolic associated fatty liver disease, hepatocellular carcinoma, acute liver failure, and alcoholic liver disease, and the related targets of FSP1 are expected to become a potential treatment option. This article comprehensively reviews FSP1, with a focus on the role of FSP1 in the pathophysiology of several common liver diseases and the potential of FSP1 as a target of liver diseases, in order to provide new ideas for the treatment of liver diseases.

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