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BACKGROUND/AIMS: Accumulating evidences have shown an important role of circular RNAs (circRNAs) in the tumorigenesis of gastric cancer (GC). Nevertheless, whether circSNX27 plays a role in GC remains undetermined. MATERIALS AND METHODS: Relative expression of circRNAs and related microRNAs (miRNAs) in GC tissues and cells were tested by quantitative reverse transcription polymerase chain reaction. Specific short hairpin RNAs were designed to knockdown the expression of circSNX27 in GC cells. CCK-8, colony formation, flow cytometry, wound healing, and transwell assays were used to access the function of circSNX27 silencing on GC cells. The target miRNAs of circSNX27 were predicted by 2 databases, circBank and Circinteractome. Dualluciferase reporter assay was used to verify the interaction between circSNX27 and miR-638. RESULTS: circSNX27 was found to be upregulated in GC tissues and cell lines compared with normal controls. Silencing of circSNX27 repressed GC cell viability, proliferation, migration, and invasion. Moreover, circSNX27 silencing could accelerate GC cell apoptosis. Additionally, we found that circSXN27 decreased the expression of miR-638 by directly binding to it in GC cells. CONCLUSION: Our results indicated that circSXN27 facilitated GC progression by acting as a sponge of miR-638.
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Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , MicroARNs , ARN Circular , Nexinas de Clasificación , Neoplasias Gástricas , Humanos , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Regulación hacia Arriba , Nexinas de Clasificación/genéticaRESUMEN
To cope with the damage from oxidative stress caused by hypoxia, mammals have evolved a series of physiological and biochemical traits, including antioxidant ability. Although numerous research studies about the mechanisms of hypoxia evolution have been reported, the molecular mechanisms of antioxidase-related genes in mammals living in different environments are yet to be completely understood. In this study, we constructed a dataset comprising 7 antioxidase-related genes (CAT, SOD1, SOD2, SOD3, GPX1, GPX2, and GPX3) from 43 mammalian species to implement evolutionary analysis. The results showed that six genes (CAT, SOD1, SOD2, SOD3, GPX1, and GPX3) have undergone divergent evolution based on the free-ratio (M1) model. Furthermore, multi-ratio model analyses uncovered the divergent evolution between hypoxic and non-hypoxic lineages, as well as various hypoxic lineages. In addition, the branch-site model identified 9 positively selected branches in 6 genes (CAT, SOD1, SOD2, SOD3, GPX2, and GPX3) that contained 35 positively selected sites, among which 31 positively selected sites were identified in hypoxia-tolerant branches, accounting for 89% of the total number of positively selected sites. Interestingly, 65 parallel/convergent sites were identified in the 7 genes. In summary, antioxidase-related genes are subjected to different selective pressures among hypoxia-tolerant species living in different habitats. This study provides a valuable insight into the molecular evolution of antioxidase-related genes in hypoxia evolution in mammals.
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OBJECTIVES: To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. METHODS: Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. RESULTS: Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). CONCLUSIONS: Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.
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Glioma , Compuestos de Fenilurea , Proteínas Tirosina Quinasas , Pirazoles , Pirimidinas , Adulto , Humanos , Bevacizumab , Glioma/tratamiento farmacológico , Progresión de la EnfermedadRESUMEN
Abstract Objectives To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. Methods Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. Results Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). Conclusions Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.
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The icing of transmission conductor seriously threatens the safe operation of power grids. Slippery lubricant-infused porous surface (SLIPS) has shown great potential for anti-icing applications. However, aluminum stranded conductors have complex surfaces, and the current SLIPSs are almost prepared and studied on small flat plates. Herein, the construction of SLIPS on the conductor was realized through anodic oxidation and the anti-icing mechanism of the slippery conductor was studied. Compared to the untreated conductor, the SLIPS-conductor reduces the icing weight by 77% in the glaze icing test and shows very low ice-adhesion strength (7.0 kPa). The excellent anti-icing performance of the slippery conductor is attributed to the droplet impact dynamics, icing delay, and lubricant stability. The dynamic behavior of water droplets is most affected by the complex shape of the conductor surface. Specifically, the impact of the droplet on the conductor surface is asymmetric and the droplet can slide along the depression in low-temperature and high-humidity environments. The stable lubricant of SLIPS increases both the nucleation energy barriers and the heat transfer resistance, which greatly delays the freezing time of droplets. Besides, the nanoporous substrate, the compatibility of the substrate with the lubricant, and the lubricant characteristics contribute to the lubricant stability. This work provides theoretical and experimental guidance on anti-icing strategies for transmission lines.
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Slippery liquid-infused porous surfaces (SLIPSs) are widely used as an effective passive approach to reduce icing disasters. However, various porous structures make SLIPSs exhibit different droplet mobility and lubricant stability. Undoubtedly, the substrate surface has a great impact on the durable anti-icing of SLIPSs. Herein, surfaces with different pore sizes and porosities were prepared to study their effects on the performance of SLIPS. The results show that small pores and high porosity are beneficial for the preparation of durable anti-icing SLIPS. The small pore size (about 100 nm) has a strong capillary pressure on the lubricant, and the surface with high porosity (66%) possesses a large lubricant-liquid contact ratio. These two can greatly improve the lubricant stability of SLIPS and achieve rapid self-healing. The SLIPS prepared by a suitable porous surface shows excellent anti-icing performance in the simulated glaze ice and durable anti-icing ability in the long-term icing/deicing cycles. In detail, the prepared SLIPS experiences more than 140 icing/deicing cycles through four effective self-healing while maintaining extremely low ice adhesion (<20 kPa). This work proposes a certain improved SLIPS with small pores and high porosity to achieve excellent durable anti-icing performance, broadening the practical applications of SLIPS.
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The dormancy-associated MADS-box (DAM) gene DAM5 has crucial roles in bud endodormancy; however, the molecular regulatory mechanism of PpDAM5 in peach (Prunus persica) has not been elucidated. In this study, using yeast two-hybrid screening, we isolated a BTB-TAZ Domain Protein PpBT3, which interacts with PpDAM5 protein, in the peach cultivar 'Chun xue'. As expected, we found that abscisic acid (ABA) maintained bud endodormancy and induced expression of the PpDAM5 gene, and that over-expressing PpDAM5 in Arabidopsis thaliana repressed seed germination. In contrast, over-expressing PpBT3 in A. thaliana promoted seed germination, and conferred resistance to ABA-mediated germination inhibition. Additionally, a qRT-PCR (quantitative real-time polymerase chain reaction) experiment suggested that the transcript level of PpBT3 gradually increased towards the endodormancy release period, which is the opposite trend of the expression pattern of PpDAM5. Our results suggest that PpBT3 modulates peach bud endodormancy by interacting with PpDAM5, thus revealing a new mechanism for regulating bud dormancy of perennial deciduous trees.
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Flores/efectos de los fármacos , Flores/metabolismo , Proteínas de Plantas/metabolismo , Prunus persica/efectos de los fármacos , Prunus persica/metabolismo , Ácido Abscísico/farmacología , Flores/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/genética , Proteínas de Plantas/genética , Prunus persica/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial production had to be developed for sacubitril. The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art technologies allowed to efficiently build up the structure of sacubitril and achieve the defined performance targets.
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Aminobutiratos , Antagonistas de Receptores de Angiotensina , Biocatálisis , Compuestos de Bifenilo , Combinación de Medicamentos , Humanos , Tetrazoles , ValsartánRESUMEN
Lonicera japonica has been used in traditional Chinese medicine as an important medicinal plant, with the ability to inhibit osteoclast development and bone loss. However, it is not clear which active ingredient exerts these effects. (R)dehydroxyabscisic alcohol ßDapiofuranosyl(1Ë®â6')ßDglucopyranoside (DAG) is an active constituent isolated from Lonicera japonica. In the present study, the ST2 bone marrow stromal cell line was treated by DAG at different concentrations and the osteoblastic differentiation was explored by ELISA assay, Von Kossa staining, Alizarin Red S staining, reverse transcriptionquantitative polymerase chain reaction and western blot analysis. The results revealed that DAG promoted osteoblastic differentiation, as evidenced by increasing mineralization and alkaline phosphatase (ALP) activity, as well as the expression of genes encoding bone differentiation markers, including Alp, osteopontin (Opn) and osteocalcin (Ocn). In addition, DAG upregulated the gene expression of bone morphogenetic protein (Bmp)2, Bmp4, Wnt family member (Wnt)1, Wnt3 and runtrelated transcription factor 2 (Runx2), as well as the protein expression of phosphorylatedmothers against decapentaplegic homolog (Smad) 1, Smad5 Smad8, ßcatenin and Runx2 in ST2 cells. The osteogenic effects induced by DAG were attenuated by the BMP antagonist Noggin and the WNT signaling pathway inhibitor Dickkopf related protein1. The data indicated that DAG promoted the osteoblastic differentiation of ST2 cells, at least partially through regulating the BMP/WNT signaling pathways. This provides scientific rationale for the development of DAG as a treatment for bone lossassociated diseases, such as osteoporosis.
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Proteína Morfogenética Ósea 2/metabolismo , Diferenciación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Oximas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Biomarcadores/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
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Antivirales/química , Ciclosporina/química , Hepacivirus/fisiología , Antivirales/síntesis química , Antivirales/farmacología , Ciclización , Ciclosporina/síntesis química , Ciclosporina/farmacología , Dipéptidos/síntesis química , Dipéptidos/química , Diseño de Fármacos , Quinidina/química , Estereoisomerismo , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Upper tract urinary carcinoma (UTUC) is a relatively uncommon but aggressive disease. The Ki-67 antigen is a classic marker of cellular proliferation, but there is still controversy regarding the significance and importance of Ki-67 in tumor progression. METHODS: In this study, we first detected Ki-67 expression in UTUC patients by immunohistochemistry (IHC). Subsequently, we quantitatively combined the results with those from the published literature in a meta-analysis after searching several databases. RESULTS: IHC results demonstrated that patients with muscle-invasive tumors (T2-T4) had higher Ki-67 expression than those with non-muscle-invasive tumors (Tis-T1), suggesting that high Ki-67 expression may be associated with the aggressive form of UTUC. Kaplan-Meier curves showed that patients with high Ki-67 expression had significantly poorer cancer-specific survival (CSS) and disease-free survival (DFS). Furthermore, multivariate analysis suggested that Ki-67 expression was an independent prognostic factor for CSS (hazard ratio, HR=3.196) and DFS (HR=3.517) in UTUC patients. Then, a meta-analysis of the published literature investigating Ki-67 expression and its effects on UTUC prognosis was conducted. After searching the PubMed, Medline, Embase, Cochrane Library and Scopus databases, 12 articles met the eligibility criteria for this analysis. The eligible studies included a total of 1740 patients with a mean number of 82 patients per study (range, 38-475). The combined results showed that increased Ki-67 levels were associated with poor survival and disease progression, with a pooled HR estimate of 2.081 and 2.791, respectively. In subgroup analysis, the pooled HR was statistically significant for cancer-specific survival (HR=2.276), metastasis-free survival (HR=3.008) and disease-free survival (HR=6.336). CONCLUSIONS: In conclusion, high Ki-67 expression was associated with poor survival in patients with UTUC, as well as a high risk of disease progression, although these findings need to be interpreted with caution. Large-scale, adequately designed, prospective trials are needed to further confirm the value of Ki-67 in prognosis of UTUC patients.
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Biomarcadores de Tumor/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Urológicas/metabolismo , Anciano , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Neoplasias Urológicas/patología , Neoplasias Urológicas/cirugíaRESUMEN
OBJECTIVE: To optimize the prescription dose of Mahuang decoction in a multi-target manner, in order to provide reference for the quantitative optimization of the prescription dose of the traditional Chinese medicine compound. METHOD: The number of diaphoretic spots in rats, the tracheal antispasmodic rate in guinea pigs and the writhing times by acetic acid in mice were taken as the indexes for evaluating the diaphoretic, antispasmodic and analgesic effects. According to the experimental results of the 16 orthogonal combination prescriptions, a mathematical dose-effect model was built by support vector regression (SVR) and quadratic response surface regression (RSR) respectively. The multi-target optimization was achieved by elitist non-dominated sorting genetic algorithm (NSGA-II) and entropy weight TOPSIS method. RESULT: The optimal dose of Mahuang decoction after being optimized by SVR modeling contained 17.71 g of Ephedrae Herba, 9.57 g of Cinnamomi Ramulus, 11.75 g of Armeniacae Semen Amarum and 4.39 g of Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle. The optimized result by RSR modeling contained 13.37 g of Ephedrae Herba, 11.61 g of Cinnamomi Ramulus, 11.98 g of Armeniacae Semen Amarum and 5.67 g of Glycyrrhizae Radix et Rhizoma Praeparate Cum Melle. SVR was superior to RSR in both of the forecast capacity and optimization results. CONCLUSION: SVR-NSGA-II-TOPSIS method could be adopted for the multi-target optimization for the dose of Mahuang decoction and other traditional Chinese medicine compounds. It is proved to be the optimal prescription with the best efficacy, and could provide scientific quantitative basis for determining the dose of traditional Chinese medicine compound prescriptions and developing new traditional Chinese medicines.
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Cinnamomum/química , Composición de Medicamentos/métodos , Ephedra sinica/química , Ephedra/química , Glycyrrhiza/química , Animales , Cálculo de Dosificación de Drogas , Prescripciones de Medicamentos , Cobayas , Ratones , RatasRESUMEN
OBJECTIVE: To investigate the expression of acidic fibroblast growth factor (aFGF) in transgenic safflower and lay the foundation for the use of the plant bioreactor large-scale production aFGF. METHOD: The haFGF gene was transformed into plant preference of the aFGF sequence as a basis for design of primers, plant preferences aFGF gene sequences was amplified by PCR. The vegetable body expression vector was constructed by using digested connection method and then transferred to Agrobacterium tumefaciens EHA105 by the freeze-thaw method. It transferred to safflowers by agrobacterium-mediated transformation method, and identified by PCR, southern blot and RT-PCR. RESULT: The full-length aFGF gene sequences were amplified through PCR and constructed into plant expression vector with soybean oleosin and promoter, and transformed into safflower. Three independently transformed safflower plant units with point insertion were successfully obtained, which showed the same size of aFGF expression at the transcriptional level. CONCLUSION: The plant oil body expression vectors were successfully constructed, and the optimal condition for genetic transformation was selected. The transgenic safflower plants were obtained.
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Carthamus tinctorius/genética , Factor 1 de Crecimiento de Fibroblastos/genética , Proteínas de la Membrana/genética , Proteínas de Plantas/genética , Transformación Genética , Agrobacterium tumefaciens/genética , Regulación de la Expresión Génica de las Plantas , Vectores Genéticos , Humanos , Plantas Modificadas Genéticamente , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To elucidate whether the antigen-processing gene (LMP2/LMP7) polymorphisms could influence the infection of hepatitis B virus. METHODS: Genomic DNA of 176 patients infected with HBV and 208 healthy volunteers were extracted from the peripheral blood leukocytes. Polymorphisms of LMP genes in HBV patients were determined by polymerase chain reaction-restriction fragment length polymorphism (RFLP), the controls by DNA sequencing. We used the software PHASE1.0 to construct the haplotypes of every individual. At last the unconditional Logistic regression model was used to analyze the statistical association of genotypes or haplotypes in two groups adjusted by gender and age. RESULTS: The distributions of LMP2 genes between cases and controls did not differ. However, LMP7 gene frequency in patients was higher than that in controls [odds ratio 2.11(95% confidence interval 1.36-3.26); 2.66 (95% confidence interval 1.17-6.02), heterogenous or homologous respectively]. Similarly, we found the haplotype combinated by R-K had a significant difference in two groups [odds ratio 1.81 (95% confidence interval 1.19-2.76)]. CONCLUSION: These findings suggest that polymorphisms of LMP2/LMP7 gene is one of the important host factors which independently affect on the infection of hepatitis B virus.