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1.
Bioengineered ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34720049

RESUMO

Bladder cancer (BC) is one of the most common malignant tumors in the urinary system. Our research aimed to explore the function and underlying mechanisms of long noncoding RNA (lncRNA) PSMA3-AS1 in BC. RT-qPCR was utilized to detect the levels of PSMA3-AS1, miR-214-5p, and PD-L1. ChIP assay was employed to confirm the transcription factor of PSMA3-AS1. Luciferase reporter assay was carried out to demonstrate the relationships between miR-214-5p and PSMA3-AS1 or PD-L1. The diagnostic value of PSMA3-AS1 was evaluated by the ROC curve. CCK-8, wound healing, transwell, and flow cytometry assays were applied to analyze cell viability, migration, invasion, and apoptosis. Western blotting was used to confirm the expression of cleaved caspase-3. The present study revealed that BC tissues and cells exhibited an increased expression in PSMA3-AS1. High expression of PSMA3-AS1 was related to poor prognosis in BC patients. Then, the area under the ROC curve for PSMA3-AS1 was up to 0.8954. Moreover, ChIP assay elaborated that YY1 could bind to the PSMA3-AS1 promoter region. Furthermore, it was found that that PSMA3-AS1 knockdown repressed BC cell viability and metastasis, and promoted apoptosis. In addition, miR-214-5p was inversely correlated with PSMA3-AS1 or PD-L1 levels. MiR-214-5p deletion reversed the impacts of PSMA3-AS1 deletion on BC progression, and PD-L1 inhibition also abrogated the influence of miR-214-5p deletion in BC development. In conclusion, YY1-induced PSMA3-AS1 exerted an oncogenic function in BC cells via targeting miR-214-5p and enhancing PD-L1, providing potential biomarkers for BC therapy.

2.
Br J Clin Pharmacol ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34729817

RESUMO

OBJECTIVES: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. METHODS: The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesis available evidence. A multicenter cross-sectional study was conducted by questionnaires to evaluate patients' perception and willingness on individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. RESULTS: Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to administration (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), management of toxicities. Of them, 12 are strong recommendations. CONCLUSIONS: We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX administration to health care providers.

3.
Nat Prod Rep ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34816854

RESUMO

Covering: March 2010 to December 2020. Previous review: Nat. Prod. Rep., 2011, 28, 705This review summarizes the latest progress and perspectives on the structural classification, biological activities and mechanisms, metabolism and pharmacokinetic investigations, biosynthesis, chemical synthesis and structural modifications, as well as future research directions of the promising natural withanolides. The literature from March 2010 to December 2020 is reviewed, and 287 references are cited.

4.
Dis Markers ; 2021: 4251763, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804261

RESUMO

Objective: Due to the molecular heterogeneity of gastric cancer, only minor patients respond to immunotherapeutic schemes. This study is aimed at developing an immune-based gene signature for risk stratification and immunotherapeutic efficacy assessment in gastric cancer. Methods: An immune-based gene signature was developed in gastric cancer by LASSO method in the training set. The predictive performance was validated in the external datasets. KEGG pathways related to risk scores were assessed by GSEA. Based on multivariate Cox regression analysis, a nomogram was established. Sensitivity to chemotherapy drugs was evaluated between high- and low-risk samples. The relationships of risk scores with infiltration levels of immune cells, stromal scores, immune scores, immune cell subgroups, and overall response to anti-PD-L1 therapy were determined. Results: Our results showed that high risk scores were indicative of undesirable survival outcomes both in the training set (p < 0.0001) and the validation set (p = 0.002). Moreover, this signature could independently predict patients' survival (HR: 2.656 (1.919-3.676) and p < 0.001). Subgroup analysis confirmed the sensitivity of this signature in predicting prognosis (all p < 0.05). Cancer-related pathways were primarily enriched in high-risk samples, such as MAPK and TGF-ß pathways (p < 0.05). By incorporating stage and the risk score, we established a nomogram for predicting one-, three-, and five-year survival probability. Patients with high-risk scores were more sensitive to chemotherapy drugs (p < 0.05). There was heterogeneity in immune cells between high- and low-risk samples (p < 0.05). Samples with progressive disease exhibited the highest risk score, and those with complete response had the lowest risk score (p < 0.05). Conclusion: This immune-based gene signature might be representative of a promising prognostic classifier for predicting risk stratification and immunotherapeutic efficacy in gastric cancer, assisting personalized therapy and follow-up plan.

5.
Transl Androl Urol ; 10(9): 3646-3655, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34733660

RESUMO

Background: To study the incidence of metabolic syndrome (MetS) and kidney stones in a healthy screening population and to explore the correlation between them. Methods: The physical examination data of 11,827 people screened at the First Affiliated Hospital of Soochow University from August 2019 to July 2020 were analyzed. MetS diagnostic criteria were based on the 2004 guidelines of Chinese Diabetes Society (CDS). Multivariate logistic regression was used to analyze the correlation between MetS and various characteristics and kidney stones. Trend analysis was represented by P value, and P<0.05 indicated statistical significance. Results: The present study comprised 6,570 males (55.6%, aged 46.15±13.653 years) and 5,257 females (44.4%, aged 41.41±11.712 years). Of these, 1,036 (8.8%) had kidney stones and 1,552 (13.1%) had MetS. Among the MetS patients, 35.1% had a body mass index (BMI) ≥25, 27.7% had hypertension, 10.8% had hyperglycemia, and 31.2% had dyslipidemia. Kidney stone morbidity was 14.5% in the MetS group and 7.9% in the non-MetS group (P<0.05). As the number of MetS characteristics increased, kidney stone morbidity showed a linear increasing trend (P<0.05 for trend). With an increase in BMI and blood triglycerides (TG), and a decrease in lipoprotein cholesterol (HDL-C), the incidence of kidney stones had an increasing trend (P<0.05 for trend). Sex, age and MetS were independent risk factors for the occurrence of kidney stones, with and odds ratio (OR) of 1.493 [95% confidence interval (CI): 1.264-1.763] for MetS. Of the MetS characteristics, BMI ≥25 and blood pressure (BP) ≥140/90 mmHg were independent risk factors for kidney stones, with OR values of 1.209 (95% CI: 1.047-1.396) and 1.248 (95% CI: 1.071-1.453), respectively. Conclusions: MetS is an independent risk factor for kidney stones. Appropriate medication and dietary advice may help to correct urinary metabolic abnormalities and prevent the recurrence of kidney stones.

6.
Chem Biodivers ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34752017

RESUMO

Many stilbene glycosides can alleviate skin hyperpigmentation due to their inhibitory effect on tyrosinase. Mulberrosides in Morus alba L. are stilbene glycosides. In the present study, the inhibition of tyrosinase by five mulberrosides( S1-5), isolated from Morus alba L. was investigated and compared, and the inhibitory mechanism was explored. These five mulberrosides exhibited obvious inhibitory effects on tyrosinase only in a concentration-dependent manner, without time-dependence, indicating that they are reversible inhibitors of tyrosinase. S2, S1 and S5 inhibited tyrosinase activity with IC50 values of 28.93, 75.94 and 151.72 µM, respectively, and were more active than kojic acid (IC50=169.13 µM). Kinetic studies revealed that S1, S2 and S4 were competitive inhibitors, while S3 and S5 were mixed  inhibitors. Analysis of the fluorescent spectra showed that mulberrosides S1, S2 and S4 quenched the intrinsic fluorescence intensity of tyrosinase. A molecular docking study indicated that the interaction of tyrosinase with mulberrosides was reflected by compound scores as follows: S2 > S5 >S1 > S3/S4 > kojic acid, and hydroxyl groups in the side chain of mulberrosides may play a crucial role in the binding of the enzyme. Our results suggest that mulberrosides in Morus alba L. could be further developed as whitening agents for enhanced performance against hyperpigmentation.

7.
8.
Bioorg Chem ; 118: 105478, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34800885

RESUMO

Linderane (LDR) is a main furan-containing sesquiterpenoid of the common herbal medicine Lindera aggregata (Sims) Kosterm. Our early study indicated that LDR led to mechanism-based inactivation (MBI) of CYP2C9 in vitro, implying possible drug-drug interactions (DDIs) in clinic. In the present study, influence of LDR on the pharmacokinetics of the corresponding hydroxylated metabolites of CYP2C9 substrates in rats was investigated. Pharmacokinetic studies revealed that pretreatment with LDR at 20 mg/kg for 15 days inhibited the metabolism of both tolbutamide and warfarin catalyzed by CYP2C9. As for 4-hydroxytolbutamide, the Cmax was decreased, the t1/2z was prolonged, and the Vz/F was increased, all with significant difference. As for 7-hydroxywarfarin, the AUC0-t/AUC0-∞ and CLz/F were significantly decreased and increased, respectively. Furthermore, the underlying molecular mechanisms based on MBI of CYP2C9 by LDR were revealed. Two reactive metabolites of LDR, furanoepoxide and γ-ketoenal intermediates were identified in CYP2C9 recombinant enzyme incubation systems. Correspondingly, covalent modifications of lysine and cysteine residues of CYP2C9 protein were discovered in the CYP2C9 incubation system treated with LDR. The formation of protein adducts exhibited obvious time- and dose-dependence, which is consistent with the trend of enzyme inhibition caused by LDR in vitro. In addition to the apoprotein of CYP2C9, the heme content was significantly reduced after co-incubation with LDR. These data revealed that modification of both apoprotein and heme of CYP2C9 by reactive metabolites of LDR led to MBI of CYP2C9, therefore resulting in the inhibition of biotransformation of CYP2C9 substrates to their corresponding metabolites in vivo.

9.
Front Chem ; 9: 761609, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660543

RESUMO

In recent years, biologically active natural products have gradually become important agents in the field of drug research and development because of their wide availability and variety. However, the target sites of many natural products are yet to be identified, which is a setback in the pharmaceutical industry and has seriously hindered the translation of research findings of these natural products as viable candidates for new drug exploitation. This review systematically describes the commonly used strategies for target identification via the application of probe and non-probe approaches. The merits and demerits of each method were summarized using recent examples, with the goal of comparing currently available methods and selecting the optimum techniques for identifying the targets of bioactive natural products.

10.
Opt Express ; 29(16): 25543-25551, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34614884

RESUMO

Spatial light modulators (SLMs) are important for various applications in photonics, such as near-infrared imaging, beam steering and optical communication. After decades of advances, current commercial devices are typically limited to kilohertz modulating speeds. To realize higher operating speeds, an electro-optic (EO) polymer and silicon nitride hybrid SLM has been demonstrated in this work. We utilize a specially designed metasurface to support a relatively high quality resonance and simultaneously confine most of the incident light in the active EO polymer layer. Combing with the high EO coefficient of the polymer, a clear modulation at 10 MHz with a driving voltage of Vp-p=±10 V has been observed in the proof-of-concept device. Our first-generation device leaves vast room for further improvement and may open an attractive route towards compact SLM with an RF modulation higher than 100 GHz.

11.
J Am Coll Cardiol ; 78(19): 1863-1871, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34696957

RESUMO

BACKGROUND: Survivors of acute type A aortic dissection (ATAAD) repair remain at risk for long-term complications. Guidelines recommend postoperative imaging surveillance, but adherence is uncertain. OBJECTIVES: The aim of this study was to define the real-world frequency of postoperative imaging and characterize long-term outcomes of ATAAD. METHODS: Population-based administrative health databases for Ontario, Canada, were linked to identify patients who underwent ATAAD repair and survived at least 90 days. Guideline-directed imaging surveillance (GDIS) was defined as undergoing a computed tomographic or magnetic resonance imaging scan at 6 and 12 months postoperatively and then annually thereafter. Multivariable time-to-event analysis explored the associations between GDIS and all-cause mortality and reintervention. RESULTS: A total of 888 patients who survived urgent ATAAD repair between April 1, 2005, and March 31, 2018, were included. Median follow-up after ATAAD repair was 5.2 years (interquartile range: 2.4-7.9 years). A total of 14% patients received GDIS throughout follow-up. At 6 years, 3.9% of patients had received GDIS. The mortality rate was 4% at 1 year, 14% at 5 years, and 29% at 10 years. Incidence of aortic reintervention was 3% at 1 year, 9% at 5 years, and 17% at 10 years; the majority of these were urgent (68%), and they carried a 9% 30-day mortality rate. Greater adherence to GDIS was associated with mortality (hazard ratio: 1.08; 95% confidence interval: 1.05-1.11) and reintervention (hazard ratio: 1.04; 95% confidence interval: 1.01-1.07). CONCLUSIONS: Adherence to GDIS following ATAAD repair is poor, while long-term mortality and reinterventions remain substantial. Further research is needed to determine if guidelines should be modified.

12.
Can J Cardiol ; 37(10): 1547-1554, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34600793

RESUMO

BACKGROUND: The novel SARS-CoV-2 (COVID-19) pandemic has dramatically altered the delivery of healthcare services, resulting in significant referral pattern changes, delayed presentations, and procedural delays. Our objective was to determine the effect of the COVID-19 pandemic on all-cause mortality in patients awaiting commonly performed cardiac procedures. METHODS: Clinical and administrative data sets were linked to identify all adults referred for: (1) percutaneous coronary intervention; (2) coronary artery bypass grafting; (3) valve surgery; and (4) transcatheter aortic valve implantation, from January 2014 to September 2020 in Ontario, Canada. Piece-wise regression models were used to determine the effect of the COVID-19 pandemic on referrals and procedural volume. Multivariable Cox proportional hazards models were used to determine the effect of the pandemic on waitlist mortality for the 4 procedures. RESULTS: We included 584,341 patients who were first-time referrals for 1 of the 4 procedures, of whom 37,718 (6.4%) were referred during the pandemic. The pandemic period was associated with a significant decline in the number of referrals and procedures completed compared with the prepandemic period. Referral during the pandemic period was a significant predictor for increased all-cause mortality for the percutaneous coronary intervention (hazard ratio, 1.83; 95% confidence interval, 1.47-2.27) and coronary artery bypass grafting (hazard ratio, 1.96; 95% confidence interval, 1.28-3.01), but not for surgical valve or transcatheter aortic valve implantation referrals. Procedural wait times were shorter during the pandemic period compared with the prepandemic period. CONCLUSIONS: There was a significant decrease in referrals and procedures completed for cardiac procedures during the pandemic period. Referral during the pandemic was associated with increased all-cause mortality while awaiting coronary revascularization.

13.
Molecules ; 26(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34641555

RESUMO

Folate is a vitamin beneficial for humans that plays an important role in metabolism, but it cannot be well supplemented by food; it is necessary to supplement it in other ways. Based on this consideration, a novel crystal form C of 6S-5-methyltetrahydrofolate calcium salt (MTHF CAC) was obtained. To explore the difference between MTHF CAC and the crystal form Ⅰ of 6S-5-methyltetrahydrofolate calcium salt (MTHF CA) as well as an amorphous product of 6S-5-methyltetrahydrofolate glucosamine salt (MTHF GA), their stability and pharmacokinetic behaviours were compared. The results of high-performance liquid chromatography coupled with ultraviolet detection analysis indicated that MTHF CAC showed a better stability than MTHF CA and MTHF GA. After oral administration of MTHF CAC, MTHF CA, and MTHF GA to male rats, the MTHF concentrations were analysed using a validated liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were compared. The mean residence times (0-t) of MTHF CAC, MTHF CA, and MTHF GA were 3.7 ± 1.9 h, 1.0 ± 0.2 h (p < 0.01), and 1.5 ± 0.3 h (p < 0.05), respectively. The relative bioavailability of MTHF CAC was calculated to be 351% and 218% compared with MTHF CA and MTHF GA, respectively, which suggests that MTHF CAC can be better absorbed and utilized for a longer period of time.


Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Tetra-Hidrofolatos/química , Tetra-Hidrofolatos/farmacocinética , Animais , Cristalização , Estabilidade de Medicamentos , Masculino , Ratos , Ratos Sprague-Dawley
14.
Chin J Nat Med ; 19(9): 706-712, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34561083

RESUMO

One-sixth of the currently known natural products contain α, ß-unsaturated carbonyl groups. Our previous studies reported a rare C-sulfonate metabolic pathway. Sulfonate groups were linked to the ß-carbon of α, ß-unsaturated carbonyl-based natural compounds through this pathway. However, the mechanism of this type of metabolism is still not fully understood, especially whether it is formed through enzyme-mediated biotransformation or direct sulfite addition. In this work, the enzyme-mediated and non-enzymatic pathways were studied. First, the sulfite content in rat intestine was determined by LC-MS/MS. The results showed that the amount of sulfite in rat intestinal contents was from 41.5 to 383 µg·g-1, whereas the amount of sulfite in rat feed was lower than the lower limit of quantitation (20 µg·g-1). Second, the reaction kinetics of sulfite-andrographolide reactions in phosphate buffer solutions (pH 6-8) was studied. The half-lives of andrographolide ranged from minutes to hours. This was suggested that the C-sulfonate reaction of andrographolide was very fast. Third, the C-sulfonate metabolites of andrographolide were both detected when andrographolide and L-cysteine-S-conjugate andrographolide were incubated with the rat small intestine contents or sulfite, indicating that the sulfite amount in rat intestine contents was high enough to react with andrographolide, which assisted a significant portion of andrographolide metabolism. Finally, the comparison of andrographolide metabolite profiles among liver homogenate (with NADPH), liver S9 (with NADPH), small intestine contents homogenate (with no NADPH), and sulfite solution incubations showed that the C-sulfonate metabolites were predominantly generated in the intestinal tract by non-enzymatic pathway. In summary, sulfite can serve as a substrate for C-sulfonate metabolism, and these results identified non-enzymatically nucleophilic addition as the potential mechanism for C-sulfonate metabolism of compounds containing α, ß-unsaturated carbonyl moiety.

15.
Acta Pharmacol Sin ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588618

RESUMO

Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.

16.
Oncol Lett ; 22(5): 747, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34539851

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that serve a major role in neural development. CRMP5 has been identified as a biomarker of numerous cancer types, including lung cancer and glioblastoma. However, the role of CRMP5 in CRC remains unclear. In the present study, CRMP5 was characterized as a novel biomarker of poor survival in CRC. CRMP5-overexpression in CRC cells promoted cell proliferation and migration while CPMP5-knockdown decreased cell growth and migration. A novel mechanism was uncovered, by which CRMP5 regulates MAPK signaling to drive CRC cell proliferation and development. Furthermore, CRMP5-overexpression induced chemotherapy resistance and tumor recurrence in CRC. Taken together, these results demonstrated the important role of CRMP5 in the development and proliferation of CRC cells and suggested that CRMP5 may be a novel therapeutic target for CRC.

17.
CJC Open ; 3(8): 1051-1059, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34505045

RESUMO

Background: Given changes in the care and outcomes of acute myocardial infarction (AMI) patients over the past several decades, we sought to develop prediction models that could be used to generate accurate risk-adjusted mortality and readmission outcomes for hospitals in current practice across Canada. Methods: A Canadian national expert panel was convened to define appropriate AMI patients for reporting and develop prediction models. Preliminary candidate variable evaluation was conducted using Ontario patients hospitalized with a most responsible diagnosis of AMI from April 1, 2015 to March 31, 2018. National data from the Canadian Institute for Health Information was used to develop AMI prediction models. The main outcomes were 30-day all-cause in-hospital mortality and 30-day urgent all-cause readmission. Discrimination of these models (measured by c-statistics) was compared with that of existing Canadian Institute for Health Information models in the same study cohort. Results: The AMI mortality model was assessed in 54,240 Ontario AMI patients and 153,523 AMI patients across Canada. We observed a 30-day in-hospital mortality rate of 6.3%, and a 30-day all-cause urgent readmission rate of 10.7% in Canada. The final Canadian AMI mortality model included 12 variables and had a c-statistic of 0.834. For readmission, the model had 13 variables and a c-statistic of 0.679. Discrimination of the new AMI models had higher c-statistics compared with existing models (c-statistic 0.814 for mortality; 0.673 for readmission). Conclusions: In this national collaboration, we developed mortality and readmission models that are suitable for profiling performance of hospitals treating AMI patients in Canada.

18.
Exp Cell Res ; 407(2): 112807, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34487730

RESUMO

ZMYND8, an epigenetic regulator, was identified as a common oncogene across various tumors. However, little was reported about the association between ZMYND8 and bladder cancer. Besides, aberrant mechanisms that contribute to abnormal ZMYND8 expressions still remain unclear. In the current study, we first found that ZMYND8 protein levels were significantly elevated in Bca samples versus normal tissues, but not the mRNA levels. We then utilized the Cell Counting Kit-8 (CCK-8) assay, clone formation assay and transwell analysis to confirm that ZMYND8 could remarkably promote the tumor progression in vitro, including growth capacity and migration. Bioinformatic predictive analysis revealed that E3 ubiquitin ligase FBXW7 interacts directly with ZMYND8 and degrades ZMYND8 in a polyubiquitination manner. Low FBXW7 was a hazard factor for promoting and depending on accumulated ZMYND8 proteins to promote Bca progression. Gene set enrichment analysis (GSEA) further indicated that ZMYND8 was notably associated with stemness process, which was well functionally validated. Lastly, ZMYND8 deficiency was observed to inhibit tumor growth of Bca in vivo, revealing a promising translational significance in Bca treatment. In conclusion, our study for the first time provided evidence for a novel mechanism of FBXW7/ZMYND8 axis in Bca, providing therapeutic vulnerability for individualized cancer treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteína 7 com Repetições F-Box-WD/metabolismo , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitinação , Neoplasias da Bexiga Urinária/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Proteína 7 com Repetições F-Box-WD/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteólise , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Molecules ; 26(17)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34500812

RESUMO

G-quadruplexes have drawn widespread attention for serving as a potential anti-cancer target and their application in material science. Molecular dynamics (MD) simulation is the key theoretical tool in the study of GQ's structure-function relationship. In this article, we systematically benchmarked the five force fields of parmbsc0, parmbsc1, OL15, AMOEBA, and Drude2017 on the MD simulation of G-quadruplex from four aspects: structural stability, central ion channel stability, description of Hoogsteen hydrogen bond network, and description of the main chain dihedral angle. The results show that the overall performance of the Drude force field is the best. Although there may be a certain over-polarization effect, it is still the best choice for the MD simulation of G-quadruplexes.


Assuntos
Quadruplex G , Simulação de Dinâmica Molecular , Ligação de Hidrogênio , Metais/química
20.
J Leukoc Biol ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34402104

RESUMO

Stem cell-like memory T cells (Tscm), are a newly defined memory T cell subset with characteristics of long life span, consistent self-renewing, rapid differentiation into effector T cells, and apoptosis resistance. These features indicate that Tscm have great therapeutic or preventive purposes, including being applied in chimeric Ag receptor-engineered T cells, TCR gene-modified T cells, and vaccines. However, the little knowledge about Tscm development restrains their applications. Strength and duration of TCR signaling, cytokines and metabolism in the T cells during activation all influence the Tscm development via regulating transcriptional factors and cell signaling pathways. Here, we summarize the molecular and cellular pathways involving Tscm differentiation, and its clinical application for cancer immunotherapy and prevention.

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