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1.
Parasite ; 31: 32, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38912916

RESUMEN

The plerocercoid larvae of Spirometra mansoni are etiological agents of human and animal sparganosis. Annexins are proteins with important roles in parasites. However, our knowledge of annexins in S. mansoni is still inadequate. In this study, 18 new members of the Annexin (ANX) family were characterized in S. mansoni. The clustering analysis demonstrated that all the SmANXs were divided into two main classes, consistent with the patterns of conserved motif organization. The 18 SmANXs were detected at all developmental stages (plerocercoid, adult, and egg) and displayed ubiquitous but highly variable expression patterns in all tissues/organs studied. The representative member rSmANX18 was successfully cloned and expressed. The protein was immunolocalized in the tegument and parenchyma of the plerocercoid and in the tegument, parenchyma, uterus and egg shell of adult worms. The recombinant protein can bind phospholipids with high affinity in a Ca2+-dependent manner, shows high anticoagulant activity and combines with FITC to recognize apoptotic cells. Annexin gene polymorphism and conservative core motif permutation were found in both cestodes and trematodes. SmANXs also revealed high genetic diversity among Platyhelminthes of medical interest. Our findings lay a foundation for further studies on the biological functions of ANXs in S. mansoni as well as other taxa in which ANXs occur.


Title: La famille des gènes des annexines chez Spirometra mansoni (Cestoda : Diphyllobothriidae) et son schéma phylogénétique parmi les Plathelminthes d'intérêt médical. Abstract: Les larves plérocercoïdes de Spirometra mansoni sont des agents étiologiques de la sparganose humaine et animale. Les annexines sont des protéines jouant un rôle important chez les parasites. Cependant, nos connaissances sur les annexines chez S. mansoni sont encore insuffisantes. Dans cette étude, 18 nouveaux membres de la famille des annexines (ANX) ont été caractérisés chez S. mansoni. L'analyse de regroupement a démontré que tous les SmANX étaient divisées en deux classes principales, ce qui correspond aux modèles d'organisation des motifs conservés. Les 18 SmANX ont été détectées à tous les stades de développement (plérocercoïde, adulte et œuf) et présentaient des modèles d'expression omniprésents mais très variables dans tous les tissus/organes étudiés. Le membre représentatif rSmANX18 a été cloné et exprimé avec succès. La protéine a été immunolocalisée dans le tégument et le parenchyme du plérocercoïde ainsi que dans le tégument, le parenchyme, l'utérus et la coquille d'œuf des vers adultes. La protéine recombinante peut se lier aux phospholipides avec une affinité élevée de manière dépendante du Ca2+, présente une activité anticoagulante élevée et se combine avec le FITC pour reconnaître les cellules apoptotiques. Un polymorphisme du gène de l'annexine et une permutation conservatrice du motif central ont été trouvés chez les cestodes et les trématodes. Les SmANX ont également révélé une grande diversité génétique parmi les Plathelminthes d'intérêt médical. Nos résultats jettent les bases pour des études plus approfondies sur les fonctions biologiques des ANX chez S. mansoni ainsi que dans d'autres taxons dans lesquels les ANX sont présents.


Asunto(s)
Anexinas , Filogenia , Spirometra , Animales , Spirometra/genética , Anexinas/genética , Anexinas/química , Secuencia de Aminoácidos , Proteínas del Helminto/genética , Proteínas del Helminto/química , Familia de Multigenes , Humanos , Femenino , Variación Genética , Proteínas Recombinantes/genética
2.
J Med Chem ; 66(19): 13746-13767, 2023 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-37791640

RESUMEN

Metallo-ß-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic ß-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.


Asunto(s)
Carbapenémicos , Inhibidores de beta-Lactamasas , Animales , Ratones , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/química , Carbapenémicos/farmacología , Meropenem/farmacología , Ácidos Carboxílicos , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Antibacterianos/química
3.
Parasit Vectors ; 16(1): 316, 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37670335

RESUMEN

BACKGROUND: Spirometra mansoni can parasitize animals and humans through food and water, causing parasitic zoonosis. Knowledge of the developmental process of S. mansoni is crucial for effective treatment; thus, it is important to characterize differential and specific proteins and pathways associated with parasite development. METHODS: In this study, we performed a comparative proteomic analysis of the plerocercoid and adult stages using a tandem mass tag-based quantitative proteomic approach. Additionally, integrated transcriptomic and proteomic analyses were conducted to obtain the full protein expression profiles of different life cycle stages of the tapeworm. RESULTS: Approximately 1166 differentially expressed proteins (DEPs) were identified in adults versus plerocercoids, of which 641 DEPs were upregulated and 525 were downregulated. Gene Ontology (GO), Clusters of Orthologous groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that most DEPs related to genetic information processing and metabolism of energy in adults seem to be more activated. In the plerocercoid stage, compared to metabolism, genetic information processing appears more dynamic. Protein-protein interaction (PPI) revealed six key proteins (phosphomannomutase, glutathione transferase, malate dehydrogenase, cytoplasmic, 40S ribosomal protein S15, ribosomal protein L15 and 60S acidic ribosomal protein P2) that may play active roles in the growth and development of S. mansoni. Finally, the combination of transcriptomic and proteomic data suggested that three pathways (ubiquitin-mediated proteolysis, phagosome and spliceosome) and five proteins closely related to these pathways might have a significant influence in S. mansoni. CONCLUSIONS: These findings contribute to increasing the knowledge on the protein expression profiles of S. mansoni and provide new insights into functional studies on the molecular mechanisms of the neglected medical tapeworm.


Asunto(s)
Cestodos , Infecciones por Cestodos , Spirometra , Adulto , Animales , Humanos , Transcriptoma , Proteómica , Perfilación de la Expresión Génica
4.
Nat Prod Res ; : 1-7, 2023 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-37746700

RESUMEN

A new sesquiterpene glycoside, ligulariatinside A (1), along with nine known compounds, dibutyl phthalate (2), 1-O-(9Z,12Z-octadecadienoyl) glycerol (3), bis (2-ethylhexyl) phthalate (4), 4-hydroxy-3-methoxyphenylpropanol (5), dihydrosyringenin (6), caffeic acid (7), 6ß-hydroxy-7(11)-eremophilen-12,8α-olide (8), together with the mixture of 6ß,8ß-dihydroxyeremophil-7(11)-en-12,8α-olide (9) and 6ß,8α-dihydroxy-eremophil-7(11)-en-12,8ß-olide (10) were isolated from roots of L. veitchiana. Structures of these compounds were elucidated by comprehensive analyses of HRESIMS, 1D NMR, and 2D NMR spectroscopic data. Compounds 2 and 4 are not likely natural compounds but contaminants. All isolated compounds were tested for antibacterial activity. Compounds 1, 5, 6, together with the mixture of 9 and 10, showed mild activity against Vibrio anguillarum, with MIC values of 50, 50, 100, and 200 µg/mL, while compound 7 showed moderate activity against Vibrio anguillarum, with a MIC value of 25 µg/mL.

5.
J Fungi (Basel) ; 8(12)2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36547633

RESUMEN

In a study of fungi isolated from plant material in Guizhou Province, China, we identified 23 strains of Diaporthales belonging to nine species. These are identified from multigene phylogenetic analyses of ITS, LSU, rpb2, tef1, and tub2 gene sequence data coupled with morphological studies. The fungi include a new genus (Pseudomastigosporella) in Foliocryphiaceae isolated from Acer palmatum and Hypericum patulum, a new species of Chrysofolia isolated from Coriaria nepalensis, and five new species of Diaporthe isolated from Juglans regia, Eucommia ulmoides, and Hypericum patulum. Gnomoniopsis rosae and Coniella quercicola are newly recorded species for China.

6.
Front Chem ; 10: 1081319, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36583158

RESUMEN

Liquid organic hydrogen storage with N-ethylcarbazole (NEC) as a carrier is a very promising method. The use of precious metal hydrogenation catalysts restricts the development in industrial grade. Efficient and low-cost hydrogen storage catalysts are essential for its application. In this work, a Ni-Mo alloy catalyst supported by commercial activated carbon was synthesized by impregnation method, and the Ni-Mo ratio and preparation conditions were optimized. The catalyst was characterized by XRD, XPS, H2-TPR, SEM, and TEM. The results showed that the doping of Mo could dramatically promote the catalytic hydrogenation of N-ethylcarbazole by the Ni-based catalyst. More than 5.75 wt% hydrogenation could be achieved in 4 h using the Ni-Mo catalyst, and the selectivity of the fully hydrogenated product 12H-NEC could be effectively improved. This result reduces the cost of hydrogenation catalysts by more than 90% and makes liquid organic hydrogen storage a scaled possibility.

7.
Zhongguo Zhen Jiu ; 42(4): 397-401, 2022 Apr 12.
Artículo en Chino | MEDLINE | ID: mdl-35403398

RESUMEN

OBJECTIVE: To observe the clinical therapeutic effect of CO2 laser moxibustion on endometriosis related pelvic pain of cold coagulation and blood stasis. METHODS: A total of 76 patients with endometriosis related pelvic pain of cold coagulation and blood stasis were randomized into a laser moxibustion group and a sham laser moxibustion group, 38 cases in each group. In the laser moxibustion group, moxibustion was applied at bilateral Zigong (EX-CA 1) using CO2 laser moxibustion instrument. In the sham laser moxibustion group, the manipulation of moxibustion was same as the laser moxibustion group, without laser output. The treatment was given once every other day, 30 min each time, 3 times a week for 4 weeks in both groups. Before and after treatment and follow-up of 3 months after treatment, the scores of Gracely box scale (GBS) and visual analogue scale (VAS) were observed, the usage of non-steroidal anti-inflammatory drug for the duration of the treatment and the average days of taking drugs were recorded in both groups. RESULTS: Compared before treatment, the GBS and VAS scores were decreased after treatment and during follow-up in the laser moxibustion group (P<0.05), while those in the sham moxibustion group had no significant differences (P>0.05). Compared with the sham moxibustion group, the GBS and VAS scores were decreased after treatment and during follow-up (P<0.05), the cases and average days of taking drugs were less in the laser moxibustion group (P<0.05). CONCLUSION: CO2 laser moxibustion can improve the pain symptom in patients with endometriosis related pelvic pain of cold coagulation and blood stasis, and reduce the use of analgesic drugs.


Asunto(s)
Endometriosis , Moxibustión , Puntos de Acupuntura , Dióxido de Carbono , Endometriosis/complicaciones , Femenino , Humanos , Dolor Pélvico/etiología , Dolor Pélvico/terapia , Resultado del Tratamiento
8.
Appl Immunohistochem Mol Morphol ; 30(3): 215-224, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35030104

RESUMEN

Our previous studies indicate that resistance induction using first-generation tyrosine kinase inhibitors (TKIs) in lung cancer is accompanied with p120-catenin (p120ctn) cytoplasmic translocation from the membrane. However, the molecular mechanism underlying p120ctn intracytoplasmic translocation has not yet been reported. We performed immunohistochemistry to detect the correlation of p120ctn distribution with protein tyrosine phosphatase non-receptor type 12 (PTP-PEST) and p120ctn Y335 phosphorylation levels in non-small cell lung cancer (NSCLC) patients. After resistance induction using first-generation TKIs in lung cancer cells, Western blotting and substrate trapping were used to assess PTP-PEST expression and its influence on p120ctn Y335 phosphorylation, as well as the role of p120ctn Y335 phosphorylation on the association of p120ctn with E-cadherin and p120ctn membrane/cytoplasm translocation. In 197 samples collected from NSCLC patients, cytoplasmic p120ctn and enhanced p120ctn Y335 phosphorylation were associated with decreased PTP-PEST. After resistance induction using gefitinib, decreased PTP-PEST expression was accompanied by enhanced phosphorylation of p120ctn Y335 and p120ctn translocated to the cytoplasm. In gefitinib-resistant cells, PTP-PEST overexpression restrained p120ctn Y335 phosphorylation and restored membrane p120ctn expression. PTP-PEST enhanced the interaction of p120ctn with E-cadherin and elevated p120ctn membrane expression. However, increased p120ctn-Y335F mutant had no effect on p120ctn interaction with E-cadherin and membrane/cytoplasm translocation compared with the control group. In conclusion, resistance to first-generation TKIs inhibited PTP-PEST expression, which promoted p120ctn-Y335 phosphorylation and reduced the interaction of p120ctn with E-cadherin, resulting in p120ctn cytoplasmic translocation.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cateninas , Citoplasma/metabolismo , Gefitinib/farmacología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteína Tirosina Fosfatasa no Receptora Tipo 12/metabolismo , Catenina delta
9.
MycoKeys ; 91: 151-168, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36760889

RESUMEN

Eucommiaulmoides is a rare tree species in China with high medicinal and gum value. Nine strains of hyphomycetous fungi were isolated from the leaf litter of E.ulmoides in Guizhou Province. Preliminary identifications based on ITS indicated that they belong to the genus Cladosporium. Morphology and phylogenetic analyses based on the internal transcribed spacer regions (ITS) of the nrDNA, the partial translation elongation factor 1-α (tef1) gene and partial of actin (act) gene confirmed that the strains represent four species, including two novel taxa, viz., Cladosporiumeucommiae and C.guizhouense and two new substrate records for known species.

10.
J Med Chem ; 64(12): 8303-8332, 2021 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-34110158

RESUMEN

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 µM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Indazoles/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Triptófano Oxigenasa/antagonistas & inhibidores , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Encéfalo/patología , Línea Celular Tumoral , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Indazoles/síntesis química , Indazoles/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/metabolismo , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Unión Proteica , Relación Estructura-Actividad , Triptófano Oxigenasa/metabolismo
11.
Appl Immunohistochem Mol Morphol ; 29(1): 34-41, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33002893

RESUMEN

PURPOSE: Approximately 10% of gastrointestinal stromal tumors (GISTs) are devoid of KIT, PDGFRA (platelet-derived growth factor-alpha), BRAF, and SDH alterations. The aim of this study was to characterize molecular drivers in Chinese patients with quadruple-negative GISTs. PATIENTS AND METHODS: In 1022 Chinese patients with GIST, mutations of KIT and PDGFRA were analyzed by direct sequencing. Of these mutations, 142 KIT/PDGFRA wild-type (WT) GISTs were detected, and succinate dehydrogenase (SDH) deficiency was determined using immunohistochemistry analysis of succinate dehydrogenase B. In 78 KIT/PDGFRA/SDH cases, we performed targeted 425 cancer-related gene analysis using next-generation sequencing. The correlation between molecular findings and clinicopathologic features was also analyzed. RESULTS: We defined 72 quadruple-negative GISTs from enrollments. They featured nongastric localization with histologic characteristics of spindle cells and male predilection. An overall 27.78% (20/72) of quadruple-negative tumors carried TP53, and 25.00% (18/72) carried RB1 mutations, which were frequently associated with high mitotic index and large size. TP53 analyses demonstrated coexistence with mutational activation of other oncogenes in 12 of 20 cases. A total of 18 RB1-mutated cases were independent of TP53. Further, no tumors carried NF1 and BRAF mutations. CONCLUSIONS: We report the genomic analysis of Chinese quadruple-negative patients. These databases may help advance our understanding of quadruple-negative GISTs' progression. Next-generation sequencing from GISTs is feasible to provide relevant data for guiding individualized therapy.


Asunto(s)
Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Mutación , Proteínas de Neoplasias , Adulto , China , Femenino , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/metabolismo , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
12.
Appl Immunohistochem Mol Morphol ; 28(1): 49-56, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30601156

RESUMEN

BACKGROUND: The aim of this study was to compare epidermal growth factor receptor (EGFR) mutations between primary tumors and corresponding bone metastases (BMs) in lung adenocarcinoma. MATERIALS AND METHODS: In total, 115 paired primary lung adenocarcinoma and corresponding BM tumors were analyzed for EGFR mutations by Amplification Refractory Mutation System. RESULTS: EGFR mutations were detected in 61 primary lung adenocarcinomas (53.04%) and in 67 corresponding metastases (58.26%), respectively. The EGFR mutation rate was significantly higher in female and in never-smoker patients. The consistency of EGFR mutations between the 115 matched BMs and primary tumor tissue samples reached to 80.87%, and the disparity was 19.13%. Mutations in exons 19 (19-del) and 21 (point mutation L858R) were the predominant mutation type. CONCLUSIONS: The concordance rate demonstrated the feasibility of EGFR mutations in corresponding metastases using Amplification Refractory Mutation System when the primary tumor tissue is unavailable in the lung adenocarcinoma patients, and the inconsistency indicates that corresponding metastasis being screened simultaneously with the primary tumor samples may present some supplementary information for the patients.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Óseas , Neoplasias Pulmonares , Proteínas de Neoplasias , Mutación Puntual , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Anciano , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exones , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
13.
Appl Immunohistochem Mol Morphol ; 28(8): 602-610, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-31394555

RESUMEN

The p21-activated kinase (PAK) family of serine/threonine kinases plays a pivotal role in various human tumors, as supported by our previous report on the overexpressed PAK isoforms in non-small cell lung cancer (NSCLC). To better understand the role of PAKs in tumorigenesis, the authors examined PAK1 expression patterns and its significance in NSCLC. It was demonstrated by immunohistochemical staining that PAK1 was increased and localized in the cytoplasm in 151 of 207 cases. High levels of PAK1 expression correlated with a histologic type of tumor (squamous cell carcinoma), tumor node metastasis stage, and lymph nodal status. We also examined the biological role of PAK1 in lung cancer cell lines transfected with PAK1-small interfering RNA. Decreased expression of PAK1 inhibited lung cancer cell proliferation and invasion, which is the major cause of lung cancer malignancy. Downregulated expression of PAK1 hampered rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase pathway activity but did not affect Wnt/ß-catenin signaling. Our findings suggest that PAK1 is an important oncogene in NSCLC, as decreased expression of PAK1 inhibited the proliferation and invasion of NSCLC cells by blocking the ERK pathway. These results provide evidence for using PAK1 inhibition as potential anticancer therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular/genética , Neoplasias Pulmonares/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Quinasas p21 Activadas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Citoplasma/metabolismo , Regulación hacia Abajo , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , ARN Interferente Pequeño , Vía de Señalización Wnt/genética , Quinasas p21 Activadas/genética
14.
Pathol Oncol Res ; 26(1): 91-100, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31758409

RESUMEN

The aim of this study was to characterize secondary kinase mutations in Chinese patients with imatinib-resistant gastrointestinal stromal tumors (GISTs). Mutations in receptor tyrosine kinase (KIT; exons 9, 11, 13, 14, 17, and 18) and platelet-derived growth factor-alpha (PDGFRA; exons 12, 14, and 18) were analyzed by direct sequencing. After imatinib treatment, 425 cancer-related target genes were analyzed by next generation sequencing (NGS) in imatinib-resistant patients. Correlation of sequencing results with clinicopathologic features were analyzed. We identified 320 patients with secondary acquired resistance. We determined that 65.63% (210/320) of resistant patients had secondary KIT mutations in exon 13 (n = 134), exon 14 (n = 10), or exon 17 (n = 66), and 4.38% (14/320) had additional PDGFRA mutations in exon 14 (n = 3) or exon 18 (n = 11). All secondary KIT mutations were missense mutations and were mostly located in kinase domains. Ninety-six imatinib-resistant GIST patients did not have secondary KIT or PDGFRA mutations. Common independent mutation events were found in retinoblastoma protein 1 (RB1) (18/96 cases), SWI/SNF-related matrix associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) (16/96 cases), and myc-associated factor X (MAX) (10/96 cases). RB1 or SMARCB1 mutations coexisted with activation of other oncogenes in 6 or 15 cases, respectively. Multiple mutations were also seen in cases with MAX mutations. These mutations are frequently associated with clinicopathological factors. Secondary mutations of KIT/PDGFRA were the most important contributors in GISTs developing resistance to imatinib treatment. Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease. Clinical assessment of the effect of these mutations may benefit existing risk assessment models and selection of adjuvant therapies in GIST patients.


Asunto(s)
Resistencia a Antineoplásicos/genética , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Mutación/efectos de los fármacos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética
15.
Chem Commun (Camb) ; 55(93): 14074-14077, 2019 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-31696869

RESUMEN

We discovered that the function of cytochrome C can be modulated by DNA nanoribbons. Meanwhile, the interplay between the DNA nanoribbons and the native cytochrome C and the possible mechanisms are also discussed.


Asunto(s)
Citocromos c/metabolismo , ADN/metabolismo , Nanoestructuras/química , Peroxidasas/metabolismo , Animales , Catálisis , Citocromos c/química , ADN/química , Guayacol/química , Caballos , Oxidación-Reducción , Peroxidasas/química , Unión Proteica
16.
Chem Commun (Camb) ; 53(63): 8878-8881, 2017 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-28737795

RESUMEN

We discovered a promising metallo-ß-lactamase inhibitor, a DNA nanoribbon, by enzymatic kinetics and isothermal titration calorimetry evaluations. Atomic force microscopy, gel electrophoresis, competitive binding experiments, circular dichroic and thermal denaturation studies suggested that the DNA nanoribbon could bind to the enzyme through a minor groove.


Asunto(s)
ADN/farmacología , Nanotubos de Carbono/química , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , ADN/química , Inhibidores de beta-Lactamasas/química
17.
Pain ; 157(5): 1037-1044, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26761381

RESUMEN

Abnormal pain processing in the central nervous system may be related to abdominal pain in patients with Crohn's disease (CD). The purpose of this study was to investigate changes in resting-state brain activity in patients with CD in remission and its relationship with the presence of abdominal pain. Twenty-five patients with CD and with abdominal pain, 25 patients with CD and without abdominal pain, and 32 healthy subjects were scanned using a 3.0-T functional magnetic resonance imaging scanner. Regional homogeneity (ReHo) was used to assess resting-state brain activity. Daily pain scores were collected 1 week before functional magnetic resonance imaging. We found that patients with abdominal pain exhibited lower ReHo values in the insula, middle cingulate cortex (MCC), and supplementary motor area and higher ReHo values in the temporal pole. In contrast, patients without abdominal pain exhibited lower ReHo values in the hippocampal/parahippocampal cortex and higher ReHo values in the dorsomedial prefrontal cortex (all P < 0.05, corrected). The ReHo values of the insula and MCC were significantly negatively correlated with daily pain scores for patients with abdominal pain (r = -0.53, P = 0.008 and r = -0.61, P = 0.002, respectively). These findings suggest that resting-state brain activities are different between remissive patients with CD with and without abdominal pain and that abnormal activities in insula and MCC are closely related to the severity of abdominal pain.


Asunto(s)
Dolor Abdominal/etiología , Dolor Abdominal/patología , Encéfalo/diagnóstico por imagen , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/patología , Imagen por Resonancia Magnética , Adolescente , Adulto , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Oxígeno/sangre , Dimensión del Dolor , Descanso , Estadísticas no Paramétricas , Adulto Joven
18.
Int J Clin Exp Med ; 8(7): 11352-5, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26379949

RESUMEN

OBJECTIVE: To compare the difference of glycosylated hemoglobin (HbA1c) for diagnosing type 2 diabetes mellitus (T2DM) between Chinese Uyghurs and Hans in xinjiang. METHODS: we collected 707 subjects, including 456 Uyghurs and 251 Hans in Xinjiang Kashi region. All the subjects were underwent oral glucose tolerance test (OGTT) for diagnosing T2DM, at the same time their clinical biochemical markers and HbA1c levels were also measured. Then the data were analyzed, the receiver operating characteristic (ROC) curve was plotted and correlation analysis were made by SPSS 19.0 software. RESULTS: 1. The levels of body mess index (BMI), 2-hour plasma glucose (2 h PG), diastolic blood pressure (DBP) total cholestero (TC) and triglycerides (TG) were 26.6±4.75 kg/m(2), 14.3±6.2 mmol/l, 81.6±13.4 mmHg, 4.5±1.3 mmol/l and 4.3±2.8 mmol/l in Uyghurs, moreover those were higher than Hans [25.4±13.3 kg/m(2), 13.1±6.9 mmol/l, 78.4±9.9 mmHg, 2.3±2.1 mmol/l and 2.0±1.4 mmol/l, (P<0.05)]. 2. Otherwise, the optimal cut-off value for HbA1c to diagnose T2DM was 6.95% in Uyghurs. At this cut-off value, the sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR) and the area under the ROC curve (AUC) were 98.3%, 97.7%, 43.64, 0.017 and 0.997. While the optimal cut-off value was 7.05% in Hans, and, the sensitivity, specificity, +LR, -LR and AUC separately were 91.1%, 92.8%, 0.971, 12.6, 0.096 and 0.971. 3. The correlation analysis was made in two populations. It demonstrated that HbA1c was positively correlated with BMI, TC and TG in Uyghurs (r=0.138, 0.273, 0.482, P<0.05). However, in Hans, the HbA1c only was positively correlated with TG (r=0.178, P<0.05). CONCLUSION: The Uyghurs have higher metabolic markers, for example, BMI, TC, DBP and TG. It reveals that Uyghurs may have more severe insulin resistance (IR) comparing with Hans. And then, the cut-off value of HbA1c for diagnosing and screening T2DM is different between Uyghurs and Hans in Xinjiang.

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