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1.
Cell Death Dis ; 12(4): 351, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824269

RESUMO

Aberrant long-noncoding RNA (lncRNA) expression has been shown to be involved in the pathogenesis of endometrial cancer (EC). Herein, we report a novel tumor suppressor lncRNA SOCS2-AS1 in EC. Quantitative real-time PCR was performed to detect RNA expression. In situ hybridization and nuclear/cytoplasmic fractionation assays were used to detect the subcellular location. We found that SOCS2-AS1 was downregulated in EC tissues. Its reduced expression was correlated with advanced clinical stage and poor prognosis. Forced expression of SOCS2-AS1 suppressed EC cell proliferation and induced cell-cycle arrest and apoptosis. SOCS2-AS1-binding proteins were detected using RNA pull-down assay and mass spectrometry. Mechanistically, SOCS2-AS1 bound to Aurora kinase A (AURKA) and increased its degradation through the ubiquitin-proteasome pathway. In conclusion, SOCS2-AS1 may thus serve as a prognostic predictor and a biomarker for AURKA-inhibitor treatment in EC patients.

2.
Pharmacol Res ; : 105596, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33831565

RESUMO

Fibroblast growth factor 1 (FGF1) has a critical regulatory role in the development of the cardiovascular system (CVS) and is strongly associated with the progression or treatment of cardiovascular disease (CVD). However, the regulatory mechanisms of FGF1 in CVS and CVD have not yet been fully elucidated. Therefore, this review article summarized the existing literature reports on the role of FGF1 in CVS under physiological and pathological conditions. First, the expression and physiological functions of endogenous FGF1 is fully demonstrated. Then, we recognized the role of exogenous FGF1 in normal CVS and related pathological processes. Specifically, the potential signaling pathways might be mediated by FGF1 in CVD treatment is discussed in detail. In addition, the barriers and feasible solutions for the application of FGF1 are further analyzed. Finally, we highlight therapeutic considerations of FGF1 for CVD in the future. Thus, this article may be as a reference to provide some ideas for the follow-up research.

3.
Sci Rep ; 11(1): 7747, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833344

RESUMO

Evidence indicates that glucose variation (GV) plays an important role in mortality of critically ill patients. We aimed to investigate the relationship between the coefficient of variation of 24-h venous blood glucose (24-hVBGCV) and mortality among patients with acute respiratory failure. The records of 1625 patients in the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) database were extracted. The 24-hVBGCV was calculated as the ratio of the standard deviation (SD) to the mean venous blood glucose level, expressed as a percentage. The outcomes included ICU mortality and in-hospital mortality. Participants were divided into three subgroups based on tertiles of 24-hVBGCV. Multivariable logistic regression models were used to evaluate the relationship between 24-hVBGCV and mortality. Sensitivity analyses were also performed in groups of patients with and without diabetes mellitus. Taking the lowest tertile as a reference, after adjustment for all the covariates, the highest tertile was significantly associated with ICU mortality [odds ratio (OR), 1.353; 95% confidence interval (CI), 1.018-1.797] and in-hospital mortality (OR, 1.319; 95% CI, 1.003-1.735), especially in the population without diabetes. The 24-hVBGCV may be associated with ICU and in-hospital mortality in patients with acute respiratory failure in the ICU, especially in those without diabetes.

4.
Clin Transl Sci ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33835715

RESUMO

To determine the impact of initial vancomycin trough concentration (VTC) on mortality in adult patients in the intensive care unit (ICU) undergoing vancomycin therapy. During their first ICU stay, patients with initial VTC records after vancomycin treatment were recruited from the eICU Collaborative Research Database to this multicenter retrospective cohort study, and classified into four groups according to VTC: less than 10, 10-15, 15-20, and greater than 20 mg/L. Multivariable logistic regression and sensitivity analyses were performed to explore the association of VTC, as a continuous and categorical variable, with mortality. This study enrolled 7220 patients from 335 different ICUs at 208 hospitals. Multivariable logistic regression models indicated that VTC was positively correlated with ICU (odds ratio [OR], 1.028, 95% confidence interval [CI], 1.019-1.037) and hospital (OR 1.028, 95% CI, 1.020-1.036) mortalities. Moreover, compared with VTC less than 10 mg/L, VTCs of 10-15, 15-20, and greater than 20 mg/L were associated with a higher risk of ICU mortality (OR, 1.330, 95% CI, 1.070-1.653; OR, 1.596, 95% CI, 1.265-2.015; abd OR, 1.875, 95% CI, 1.491-2.357, respectively), and VTCs of 15-20 and greater than 20 mg/L were also correlated with increased hospital mortality (OR, 1.482, 95% CI, 1.225-1.793; and OR, 1.831, 95% CI, 1.517-2.210, respectively). Similar results persisted in patients with different Acute Physiology and Chronic Health Evaluation Ⅳ scores, creatinine clearance levels, ages, and body mass indexes. Our findings indicated a potential relationship of initial VTC with ICU and hospital mortalities in patients in the ICU. However, due to the retrospective nature of this study, future prospective studies or randomized controlled trials are needed to validate those results.

5.
IUBMB Life ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830627

RESUMO

BACKGROUND: Emerging evidence has shown that Long noncoding RNAs (LncRNAs) are aberrantly expressed and functionally involved in the development of neurodegenerative disorders. In this work, we investigated the regulatory effects of lncRNA of LINC01311 and its competing endogenous RNA target of hsa-miR-146a-5p in a cellular model of Alzheimer's disease (AD). METHODS: SH-SY5Y cells were treated with synthetic Βeta-Amyloid Peptide (1-42) (AB1-42) in vitro to induce AD-like neural injuries. Expressions of LINC01311 and hsa-miR-146a-5p were monitored by qRT-PCR. LINC01311 was upregulated and hsa-miR-146a-5p downregulated to examine their functional regulations on AB1-42-induced apoptosis, proliferation slowdown, autophagy and amyloid precursor protein (APP) accumulations. Hsa-miR-146a-5p was also overexpressed in LINC01311-upregulated SH-SY5Y cells to examine their correlated regulations on AB1-42-induced neural injuries. RESULTS: LINC01311 was downregulated whereas hsa-miR-146a-5p upregulated in AB1-42 treated SH-SY5Y cells. LINC01311 upregulation and hsa-miR-146a-5p downregulation protected AB1-42-induced apoptosis, proliferation slowdown, autophagy and APP accumulations in SH-SY5Y cells. Hsa-miR-146a-5p overexpression reversed the protection of LINC01311 on AB1-42-induced neural injuries. CONCLUSION: our work demonstrated that the epigenetic axis of LINC01311 / hsa-miR-146a-5p was involved in the functional regulation of human-lineage neurons in a cellular model of AD, thus suggesting a clinical potential of exploring epigenetic network for treating AD patients. This article is protected by copyright. All rights reserved.

6.
Theranostics ; 11(9): 4187-4206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754056

RESUMO

Axonal degeneration is a common pathological feature in many acute and chronic neurological diseases such as spinal cord injury (SCI). SARM1 (sterile alpha and TIR motif-containing 1), the fifth TLR (Toll-like receptor) adaptor, has diverse functions in the immune and nervous systems, and recently has been identified as a key mediator of Wallerian degeneration (WD). However, the detailed functions of SARM1 after SCI still remain unclear. Methods: Modified Allen's method was used to establish a contusion model of SCI in mice. Furthermore, to address the function of SARM1 after SCI, conditional knockout (CKO) mice in the central nervous system (CNS), SARM1Nestin-CKO mice, and SARM1GFAP-CKO mice were successfully generated by Nestin-Cre and GFAP-Cre transgenic mice crossed with SARM1flox/flox mice, respectively. Immunostaining, Hematoxylin-Eosin (HE) staining, Nissl staining and behavioral test assays such as footprint and Basso Mouse Scale (BMS) scoring were used to examine the roles of SARM1 pathway in SCI based on these conditional knockout mice. Drugs such as FK866, an inhibitor of SARM1, and apoptozole, an inhibitor of heat shock protein 70 (HSP70), were used to further explore the molecular mechanism of SARM1 in neural regeneration after SCI. Results: We found that SARM1 was upregulated in neurons and astrocytes at early stage after SCI. SARM1Nestin-CKO and SARM1GFAP-CKO mice displayed normal development of the spinal cords and motor function. Interestingly, conditional deletion of SARM1 in neurons and astrocytes promoted the functional recovery of behavior performance after SCI. Mechanistically, conditional deletion of SARM1 in neurons and astrocytes promoted neuronal regeneration at intermediate phase after SCI, and reduced neuroinflammation at SCI early phase through downregulation of NF-κB signaling after SCI, which may be due to upregulation of HSP70. Finally, FK866, an inhibitor of SARM1, reduced the neuroinflammation and promoted the neuronal regeneration after SCI. Conclusion: Our results indicate that SARM1-mediated prodegenerative pathway and neuroinflammation promotes the pathological progress of SCI and anti-SARM1 therapeutics are viable and promising approaches for preserving neuronal function after SCI.

7.
Cancer Biomark ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33780361

RESUMO

BACKGROUND: Hepatoblastoma (HB) is an embryonic solid tumor and the most common primary malignant liver tumor in children. HB usually occurs in infants and children. Although treatment diversity is increasing, some patients still have very poor prognosis. Many studies have investigated USP7 inhibitors for tumors. Using database information, we found that USP7 is highly expressed in HB. METHODS: Lentivirus-mediated USP7 knockdown and overexpression was performed in HB cell lines HepG2 and Huh6. CCK8 and transwell assays were used to determine cell viability and metastasis. Flow cytometry was used to study cell cycle and apoptosis. Levels of proteins were detected using western blots. RESULTS: Downregulation of USP7 resulted in significant decrease in cell proliferation, clonal formation, and cell migration and invasion. With overexpression of USP7, cellular malignant behavior increased. Cell cycle assays showed that USP7 knockdown inhibited G1 to S phase transition in the cell cycle. Upregulation of USP7 promoted the transition. Animal experiments showed USP7 facilitated tumor growth in vivo. Western blots indicated that USP7 may affect HB tumorigenesis through the PI3K/AKT signaling pathway. Furthermore, USP7 inhibitor P5091 inhibited HB development and PI3K/AKT pathway. CONCLUSION: USP7 upregulation contributed to HB genesis and development through the PI3K/AKT signaling pathway. USP7 could be a potential target for future HB treatment.

8.
Int J Biol Macromol ; 179: 292-298, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33652045

RESUMO

In this study, a series of chitosan derivatives bearing active halogenated aromatic imines were successfully synthesized via Schiff bases with the high degrees of substitution. Detailed structural characterization was carried out using Fourier transform infrared (FTIR) spectroscopy, solid-state 13C nuclear magnetic resonance (NMR) spectroscopy, and elemental analysis. Besides, the antifungal activity against three common plant pathogenic fungi, including Botrytis cinerea, Fusarium oxysporum f. sp. cucumerinum, and Fusarium oxysporum f. sp. niveum, was investigated using in vitro hyphal measurements. The results showed that double Schiff bases of chitosan derivatives exhibited enhanced antifungal activity compared with chitosan, especially at 1.0 mg/mL. The double Schiff bases of chitosan bearing halogeno-benzenes showed >95% inhibitory indices at 1.0 mg/mL against Botrytis cinereal since halogens had the stronger electron-withdrawing property. The higher degree of substitution was another positive effect to improve the antifungal activity. This study provides a practical strategy to synthesize new double Schiff bases of chitosan derivatives bearing halogeno-benzenes, which could be developed into stronger antifungal agents.

9.
Int J Nanomedicine ; 16: 1587-1600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664573

RESUMO

Background: Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects. Methods: HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs. Results: The optimized HTPMs had an HD of 17.8±0.5 nm and ZP of 14.40±0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility. Conclusion: The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.


Assuntos
Composição de Medicamentos , Micelas , Piperidinas/uso terapêutico , Polímeros/química , Quinazolinonas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitamina E/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/uso terapêutico , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/ultraestrutura
10.
Eur J Ageing ; : 1-10, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33758584

RESUMO

Older adults have gained great media attention during the COVID-19 pandemic, as they were believed to be vulnerable to the novel virus based on clinical data and epidemiological evidence. The high volume of media coverage played an important role in calling for improved public health services for the older population. Nevertheless, problematic media representations of older people might evoke or amplify ageism during the pandemic. Therefore, drawing on empirical data collected from five mainstream Chinese media outlets between January 3 and May 3, 2020, this study examined how the media constructed the vulnerability of older adults and its underlying ageist thinking during the pandemic. The findings showed that the media had clear preferences in constructing older people as passive recipients while seeking resources from families, public institutions and governments at various levels to cope with the COVID-19 pandemic. Notably, the media adopted a biomedical-centred framework presenting older people as a homogenous group that was vulnerable to the pandemic. In addition, we found that the media representations of older adults intensified the dichotomised relationship between the young and the old, causing the younger generations to perceive older people as a 'threat' to public health. Moving beyond the Chinese case, this article appeals to the media to be socially responsible by avoiding the stereotyping of the older population and uniting the whole society to combat COVID-19. The findings of this study will help raise awareness among policymakers and care service providers, which is crucial to eliminating ageist attitudes across society and to further allowing the values of older individuals to be fully recognised.

11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 278-281, 2021 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-33751542

RESUMO

OBJECTIVE: To explore the molecular basis for an individual with Bw subtype. METHODS: Routine serological reactions were used to determine the surface antigens of erythrocytes and antibodies in serum. PCR-sequence-based typing (PCR-SBT) was used to analyze the coding regions of the ABO gene and erythroid-specific regulatory element in its intron 1. Amplicons for exons 5 to 7 containing the variant site were subjected to TA cloning for the isolation of the haploid and verification of the sequence. The 3D structure of mutant protein was predicted with Pymol software. Changes of amino acid residues and structural stability were also analyzed. RESULTS: Serological assay showed that the individual had weakened B antigen and anti-B antibody in his serum. His genotype was determined as ABO*B.01/ABO*O.01.01. Sequencing of the entire coding region of the ABO gene identified an additional heterozygous c.734C/T variant. No variant was found in the erythroid-specific regulatory element of intron 1. Haploid cloning and isolation has obtained an ABO*O.01.01 allele and a ABO*B.01 allele containing a c.734T variant, which has led to substitution of Thr by Ile at position 245 in the functional center of glycosyltransferase. Based on the 3D structure of the protein, the residues binding with the mutation were unchanged, but the bonding distance between the hydrogens was changed with the amino acid substitution. Meanwhile, the connections with water molecules were increased. CONCLUSION: The c.734C>T variant of the GTB gene can lead to an amino acid substitution in the functional center of the enzyme, which in turn may affect the stability of glycosyltransferase B protein and reduceits enzymatic activity.


Assuntos
Sistema ABO de Grupos Sanguíneos , Glicosiltransferases , Sistema ABO de Grupos Sanguíneos/genética , Alelos , Éxons/genética , Genótipo , Glicosiltransferases/genética , Humanos , Masculino , Fenótipo
12.
J Am Heart Assoc ; 10(6): e018385, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33666090

RESUMO

Background Previous studies have suggested that sleep timing is associated with cardiovascular risk factors. However, there is no evidence on the relationship between sleep timing and congestive heart failure (CHF). We aimed to examine this relationship in this study. Methods and Results We recruited 4765 participants (2207 men; mean age, 63.6±11.0 years) from the SHHS (Sleep Heart Health Study) database in this multicenter prospective cohort study. Follow-up was conducted until the first CHF diagnosis between baseline and the final censoring date. Sleep timing (bedtimes and wake-up times on weekdays and weekends) was based on a self-reported questionnaire. Cox proportional hazard models were constructed to investigate the association between sleep timing and CHF. During the mean follow-up period of 11 years, 519 cases of CHF (10.9%) were reported. The multivariable Cox proportional hazards models revealed that participants with weekday bedtimes >12:00 am (hazard ratio [HR], 1.56; 95% CI, 1.15-2.11; P=0.004) and from 11:01 pm to 12:00 am (HR, 1.25; 95% CI, 1.00-1.56; P=0.047) had an increased risk of CHF compared with those with bedtimes from 10:01 pm to 11:00 pm. After stratified analysis, the association was intensified in participants with a self-reported sleep duration of 6 to 8 hours. Furthermore, wake-up times >8:00 am on weekdays (HR, 1.53; 95% CI, 1.07-2.17; P=0.018) were associated with a higher risk of incident CHF than wake-up times ≤6:00 am. Conclusions Delayed bedtimes (>11:00 pm) and wake-up times (>8:00 am) on weekdays were associated with an increased risk of CHF.

13.
J Nucl Med ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674401

RESUMO

The objective of this study was to assess the safety, dosimetry, and efficacy of the 177Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo (D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (177Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (age 27-76, mean 51.6±13.9 years) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1±0.88 GBq (range 2.8-7.4 GBq). 68Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after 177Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed in 11 patients and compared with the SSTR agonist 177Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life of 177Lu-DOTA-LM3 was found for whole-body as well as kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses as compared to the agonist 177Lu-DOTA-TOC. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was CTC-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of 47 patients monitored after 177Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 (14.9%) patients had progressive disease, and by EORTC criteria, complete remission in 2 (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%) patients. Conclusion: "Antagonist PRRT" with 177Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by the majority of patients, with thrombocytopenia occurring only in a few patients. No other severe adverse effects were observed, particularly no nephrotoxicity. The SSTR antagonist 177Lu-DOTA-LM3 appears to be very promising for PRRT, provides favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was very effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients.

14.
Oncogene ; 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33714986

RESUMO

Pancreatic cancer (PC) is highly malignant and has a high mortality with a 5-year survival rate of less than 8%. As a member of the roundabout immunoglobulin superfamily of proteins, ROBO1 plays an important role in embryogenesis and organogenesis and also inhibits metastasis in PC. Our study was designed to explore whether ROBO1 has effects on the proliferation of PC and its specific mechanism. The expression of ROBO1 was higher in cancer tissues than in matched adjacent tissues by immunohistochemistry (IHC) and qRT-PCR. Low ROBO1 expression is associated with PC progression and poor prognosis. Overexpression of ROBO1 can inhibit the proliferation of PC cells in vitro, and the S phase fraction can also be induced. Further subcutaneous tumor formation in nude mice showed that ROBO1 overexpression can significantly inhibit tumor growth. YY1 was found to directly bind to the promoter region of ROBO1 to promote transcription by a luciferase reporter gene assay, a chromatin immunoprecipitation (ChIP) and an electrophoretic mobility shift assay (EMSA). Mechanistic studies showed that YY1 can inhibit the development of PC by directly regulating ROBO1 via the CCNA2/CDK2 axis. Taken together, our results suggest that ROBO1 may be involved in the development and progression of PC by regulating cell proliferation and shows that ROBO1 may be a novel and promising therapeutic target for PC.

15.
Mol Med Rep ; 23(4)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33649809

RESUMO

The present study aimed to determine the role and regulatory mechanism of hydrogen sulfide (H2S) in the amelioration of doxorubicin­induced myocardial fibrosis in rats. It is hypothesized that the PI3K/AKT/mTOR signaling pathway is regulated to inhibit endoplasmic reticulum stress (ERS) and autophagy to reduce myocardial fibrosis. A total of 40 adult male Sprague Dawley rats were randomly divided into 4 groups (n=10/group). The 4 groups included the normal control group (control group), model group [doxorubicin (Dox) group], H2S intervention model group (H2S+Dox group) and H2S control group (H2S group). The model used in the present study was constructed by administering intraperitoneal injections of doxorubicin (3.0 mg/kg every other day; total of 6 injections). In addition, the intervention factor, NaHS and the donor of H2S, was also administered by intraperitoneal injection (56 µmol/kg/day), which lasted a month. Pathological changes in the rats were observed using Masson staining and transmission electron microscopy, while the protein expression levels of MMPs/TIMPs, transforming growth factor­ß1, cystathionine lyase and PI3K/AKT/mTOR, which are autophagy­related and ERS­related proteins were detected in myocardial tissues using western blot analysis. The gene expression levels of collagen type I α­2 chain and collagen type III α­1 chain were detected using reverse transcription­quantitative PCR and the quantification of myocardial H2S content was performed using ELISA. In the Dox group compared with that in the control group, myocardial fibers were significantly disordered, while the protein expression levels of ERS­related and autophagy­related proteins were increased markedly, and the expression levels of PI3K/AKT/mTOR proteins were reduced markedly. The aforementioned changes were markedly reversed following H2S intervention, which indicated that H2S exerts a positive protective effect on doxorubicin­induced myocardial fibrosis. The protective mechanism of H2S intervention in myocardial fibrosis is hypothesized to be associated with the inhibition of overactivation of the ER and that of autophagy via upregulation of the PI3K/AKT/mTOR pathway.

16.
Oxid Med Cell Longev ; 2021: 8049079, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643519

RESUMO

Traditional Chinese medicine has shown great safety and efficacy in the treatment of heart failure (HF), whereas the mechanism remains unclear. In this study, the protective effect of Yixin-shu (YXS) capsules, a conventional medicine for various cardiovascular diseases, against myocardial ischemia-induced HF in rats was systematically investigated by RNA-seq technology. HF rats treated with YXS (0.8 or 1.6 g/kg/d, ig) for 6 weeks had significantly decreased brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) and collagen III and attenuated cardiac structure rupture and collagen deposition. Additionally, YXS treatment decreased the levels of interleukin-1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and lactate dehydrogenase (LDH) and TUNEL-positive rate and the nitrotyrosine staining, but increased levels of glutathione (GSH), total antioxidant capacity (T-AOC) activity, and mitochondrial membrane potential. Further experiments demonstrated that YXS restored Trx2 and inhibited the phosphorylation of JNK and p38, thereby improving cardiac function in the rats with HF. Silencing Trx2 decreased the protection of YXS in the response to H2O2 as evidenced by the increase of caspase-3 activity and decrease of GSH level. Thus, YXS enhanced heart function and decreased myocardial damage through restoring Trx2 and inhibiting JNK and p38 activation in ischemia-induced HF.

17.
World J Gastroenterol ; 27(8): 725-736, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33716450

RESUMO

BACKGROUND: Endoscopic submucosal dissection to treat mucosal and submucosal lesions sometimes results in low rates of microscopically margin-negative (R0) resection. Endoscopic full-thickness resection (EFTR) has a high R0 resection rate and allows for the definitive diagnosis and treatment of selected mucosal and submucosal lesions that are not suitable for conventional resection techniques. AIM: To evaluate the efficacy and safety of EFTR using an over-the-scope clip (OTSC). METHODS: This prospective, single-center, non-randomized clinical trial was conducted at the endoscopy center of Shengjing Hospital of China Medical University. The study included patients aged 18-70 years who had gastric or colorectal submucosal tumors (SMTs) (≤ 20 mm in diameter) originating from the muscularis propria based on endoscopic ultrasound (EUS) and patients who had early-stage gastric or colorectal cancer (≤ 20 mm in diameter) based on EUS and computed tomography. All lesions were treated by EFTR combined with an OTSC for wound closure between November 2014 and October 2016. We analyzed patient demographics, lesion features, histopathological diagnoses, R0 resection (negative margins) status, adverse events, and follow-up results. RESULTS: A total of 68 patients (17 men and 51 women) with an average age of 52.0 ± 10.5 years (32-71 years) were enrolled in this study, which included 66 gastric or colorectal SMTs and 2 early-stage colorectal cancers. The mean tumor diameter was 12.6 ± 4.3 mm. The EFTR procedure was successful in all cases. The mean EFTR procedure time was 39.6 ± 38.0 min. The mean OTSC defect closure time was 5.0 ± 3.8 min, and the success rate of closure for defects was 100%. Histologically complete resection (R0) was achieved in 67 (98.5%) patients. Procedure-related adverse events were observed in 11 (16.2%) patients. The average post-procedure length of follow-up was 48.2 ± 15.7 mo. There was no recurrence during follow-up. CONCLUSION: EFTR combined with an OTSC is an effective and safe technique for the removal of select subepithelial and epithelial lesions that are not amenable to conventional endoscopic resection techniques.

18.
Dis Esophagus ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33786604

RESUMO

Endoscopic submucosal dissection (ESD) is an important method for the treatment of early esophageal cancer. However, post-procedure stenosis is one of the most common long-term complications. This meta-analysis aimed to investigate whether stent placement is effective in the stenosis prevention, and which type of stent would be more effective. A systematic and electronic search of clinical trials and observational studies conducted before March 2020 on the efficacy of stent placement in preventing esophageal stricture after ESD was performed. Search terms included "ESD," "esophageal stenosis," "esophageal stricture," and "stents." We conducted a bias risk assessment of the eligible reports and a meta-analysis of the data using Revman 5.3 software. We included two randomized controlled trials (RCTs) and a prospective cohort study involving 163 patients with esophageal mucosal defects encompassing at least three-quarters of the esophagus circumference after ESD. The meta-analysis results showed that post-ESD stenosis rates (RR, 0.37; 95% CI, 0.22-0.64; P = 0.0003) and the number of endoscopic balloon dilations (EBDs) (MD, -1.74; 95% CI, -2.46 to -1.01; P < 0.00001) were reduced in the pooled analysis of three studies, indicating that stent placement was effective for stenosis prevention, especially a polyglycolic acid (PGA) sheet combined with stent placement can prevent stenosis (RR, 0.41; 95% CI, 0.23-0.74; P = 0.003) and reduce the number of EBDs (MD, -1.65; 95% CI, -2.40 to -0.90; P < 0.0001) significantly. Stent placement can reduce the rate of esophageal stenosis after ESD, especially when stents are covered with PGA sheets. However, more high-quality, low-bias RCTs with a sufficient sample size are needed to demonstrate its effectiveness.

19.
Int J Biol Macromol ; 181: 572-581, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33766596

RESUMO

A series of novel inulin derivatives were designed and synthesized by the introduction of amino heterocyclic moieties onto carboxymethyl inulin with the aid of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide. The target products were prepared via three - step chemical synthesis, and structures were identified by FTIR and 1H NMR spectroscopy. Antioxidant activities of inulin derivatives including DPPH - radical scavenging assay, superoxide - radical scavenging assay, hydroxyl - radical scavenging assay, and reducing power were estimated. Meanwhile, their antifungal activities, including Colletotrichum lagenarium and Botrytis cinerea, were also explored by hyphal measurement. In particular, inulin derivatives bearing heterocyclic moieties exhibited a remarkable improvement over inulin on antioxidant and antifungal activities, and their bioactivities decreased roughly in the order of 2ATCMI > 4APCMI > 3APCMI > 2APCMI > 3ATCMI > CMI > inulin. Furthermore, the cytotoxicities of inulin derivatives against L929 cells were evaluated by CCK-8 in vitro, and all samples showed weak cytotoxicities. In a nutshell, the paper provides a practical approach to synthesize novel inulin derivatives with dramatically enhanced bioactivity and good biocompatibility. The product described in paper might serve as a new leading structure for further design of antioxidants or antifungal agents in biomedicine, cosmetics, and other fields.

20.
Int J Biol Macromol ; 181: 72-81, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33771546

RESUMO

Conventional tumor chemotherapy is limited by its low therapeutic efficacy and side effects, which severely hold back its further application as a first-line agent in clinic. To improve the cure efficacy of cancer, nanozyme with enzyme-like activity has now been extensively investigated as a new strategy for tumor treatment. Herein, an anti-tumor platform based on manganese oxides (MnOx) modified poly (lactic-co-glycolic acid) (PLGA)@polydopamine (PDA) nanoparticles (PP-MnOx NPs) as an oxidase mimic was developed. PP-MnOx NPs could not only produce abundant reactive oxygen species to inhibit tumor growth taking advantage of their oxidase-like activity, but also encapsulate and release antitumor drug (artesunate) to function as chemotherapy, achieving remarkable synergistic chemo-catalytic therapeutic effects. As an oxidase mimics, PP-MnOx NPs induced the decrease of mitochondrial membrane potential, down-regulation of Bcl-2, as well as activation of Bax and Caspase-3, demonstrating that the apoptosis triggered by PP-MnOx NPs was mediated via mitochondrial pathways. Importantly, the artesunate in PP-MnOx NPs further promoted this apoptosis. In addition, Mn ions released from PP-MnOx NPs facilitated the tumor-microenvironment-specific T1-weighted magnetic resonance imaging. Taken together, this study well clarifies the antitumor mechanism of artesunate-loaded PP-MnOx NPs and offer a synergistic chemo-catalytic strategy for tumor theranostics.

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