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1.
Eur J Med Chem ; 215: 113251, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33611187

RESUMO

Development of the drug with high therapeutic efficacy and low toxicity is crucial to cancer ablation. In this study, we have demonstrated a red light-responsive prodrug BDP-TK-CPT by connecting the chemotherapeutic agent camptothecin with a boron dipyrromethene (BDP)-based photosensitizer via a reactive oxygen species (ROS)-labile thioketal chain. Since camptothecin is modified by a BDP-based macrocycle at the active site, the formed prodrug displays an extremely low toxicity in dark. However, upon illumination by red light, it can efficiently generate ROS leading to cell death by photodynamic therapy. Meanwhile, the ROS generated can destroy thioketal group to release free camptothecin which further results in local cell death by chemotherapy. The combined antitumor effects of the prodrug have been verified in HepG2, EC109, and HeLa cancer cells and mice bearing H22 tumors. This study may provide an alternative strategy for stimuli-responsive combination treatment of tumors by conjugation of ROS-activatable prodrugs with photosensitizing agents.

2.
J Ethnopharmacol ; : 113934, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33607198

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Abietic acid (AA), an antibacterial terpenoid, was initially isolated from rosin which has been used as a traditional Chinese medicine to treat psoriasis. In our previous works, we found that water-processed rosin (WPR) can alleviate imiquimod (IMQ)-induced psoriasis-like inflammation in mice. However, the efficacy of AA, the main component of WPR, against psoriasis remains unclear. MATERIALS AND METHODS: In this study, we confirmed the anti-psoriasis efficacy of AA (40 mg/kg daily for 7 days) in IMQ-induced psoriasis-like inflammation BALB/c mouse model by the psoriasis area severity index (PASI), flow cytometry, ELISA, histopathological and immunohistochemical analysis. Furthermore, we detected the relative abundance of gut microbe using high-throughput 16S rRNA gene sequencing to validate whether AA modulate gut microbe. RESULT: Oral administration of AA ameliorates IMQ-induced psoriasis-like skin inflammation through reducing PASI scores, regulating the balance of Th17/Treg cells in the mouse spleen, and downregulating the level of serum cytokines such as TNF-α, IL-17A, TGF-1ß, and IL-23. 16S rRNA gene sequencing revealed that the relative abundance of gut bacteria related to inflammation, such as, Anaerotruncus and Christensenella at genus level were decreased, while Kurthia, Citrobacter, and Klebsiella at genus level were increased in AA group mice. Additionally, the correlation analysis illustrated that the key microbiota had a close relationship with the psoriasis-like inflammation related indexes. CONCLUSION: AA might exert the anti-psoriasis effect via inhibiting Th17-related immune responses, hinting that it might be a candidate for treating psoriasis. Meanwhile, the alteration of intestinal microbiota by AA treatment is another possible explanation for the amelioration of imiquimod-induced psoriasis-like inflammation.

3.
Med Sci Monit ; 27: e927624, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33436534

RESUMO

BACKGROUND Traditional Chinese medicine has widely used Bolbostemma paniculatum to treat diseases, including cancer, but its underlying mechanisms remain unclear. The present study aimed to elucidate the potential pharmacological mechanisms of "Tu Bei Mu" (TBM), the Chinese name for Bolbostemmatis Rhizoma, the dry tuber of B. paniculatum, for the treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS The active components and putative therapeutic targets of TBM were explored using SwissTargetPrediction, Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and Search Tool for Interactions of Chemicals (STITCH). The HCC-related target database was built using DrugBank, DisGeNet, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). A protein-protein interaction network of the common targets was constructed, based on the matches between TBM potential targets and HCC-related targets, using Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the cluster networks were used to elucidate the biological functions of TBM. RESULTS Pharmacological network diagrams of the TBM compound-target network and HCC-related target network were successfully constructed. A total of 22 active components, 191 predicted biological targets of TBM, and 3775 HCC-related targets were identified. Through construction of an HCC-related target database and a protein-protein interaction network of the common targets, TBM was predicted to be effective in treating HCC mainly through the PI3K-Akt, HIF-1, p53, and PPAR signaling pathways. CONCLUSIONS The PI3K/Akt, HIF1, p53, and PPAR pathways may play vital roles in TBM treatment of HCC. Also, the potential anti-cancer effect of TBM on HCC appears to stem from the synergetic effect of multiple targets and mechanisms.

4.
Carbohydr Polym ; 255: 117532, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436261

RESUMO

Aldolase A (ALDOA) facilitated aerobic glycolysis in cancer cells is a potential target in the treatment of hepatocellular carcinoma (HCC). However, only few effective inhibitors of ALDOA have been reported until now. In this research, we found a polysaccharide called HDPS-4II from Holotrichia diomphalia Bates, which can specifically bind to ALDOA with a dissociation constant of 2.86 µM. HDPS-4II with a molecular weight of 19 kDa was a linear triple-helix glucan composed of ɑ-d-1,4-Glcp and ɑ-d-1,6-Glcp in a ratio of 1.0:10.0. HDPS-4II significantly inhibited aldolase enzyme activity, glycolysis, and further inhibited the expression of phosphorylated AMPKα in HCC cells. Through analyzing ALDOA-overexpressing and -knockdown cells, it was confirmed that ALDOA mediated the viability and glycolysis inhibition of HDPS-4II. Moreover, HDPS-4II administration markedly inhibited tumor growth in mice xenografted with HCCs. These findings suggest that HDPS-4II, as an ALDOA antagonist, is a promising remedy in the treatment and prevention of HCC.

6.
Life Sci ; 270: 119016, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33515564

RESUMO

AIMS: Ryanodine receptor-1 (RyR1) is essential for skeletal muscle cell functions. However, its roles in vascular smooth muscle cells (SMCs) are well recognized. This study aims to determine the potential physiological importance and difference in systemic and pulmonary artery SMCs (SASMCs and PASMCs). METHODS: Local and global Ca2+ release were measured using a laser scanning confocal microscope and wide-field fluorescence microscope; membrane currents were recorded using a patch clamp recording; muscle contraction was determined using an organ bath system; RyR protein expression was assessed using immunofluorescence staining. Homozygous and heterozygous RyR1 gene knockout (RyR1-/- and RyR1+/-) mice were used to determine its specific functions. KEY FINDINGS: Ca2+ sparks were more prominently decreased in RyR1-/- ASMCs than in PASMCs. Caffeine induced a smaller increase in [Ca2+]i in both RyR1+/+ and RyR1-/- ASMCs than in PASMCs. High K+ produced a reduced [Ca2+]i increase in RyR1-/- PASMCs and ASMCs as well as a reduced contraction in RyR1+/- pulmonary artery and aortic tissues. ATP elicited a smaller increase in [Ca2+]i in RyR1-/- ASMCs and PASMCs with a greater inhibition in ASMCs. Norepinephrine-elicited muscle contraction was reduced in RyR1+/- aortic and pulmonary arteries. IP3 dialysis-induced Ca2+ release was much smaller in RyR1+/- ASMCs and PASMCs. Hypoxia-induced large Ca2+ and contractile responses were inhibited in RyR1+/- PASMCs. However, hypoxic exposure did not evoke a notable increase in [Ca2+]i in ASMCs. SIGNIFICANCE: Our findings for the first time provide clear genetic evidence for the functional importance and difference of RyR1 in systemic and pulmonary artery SMCs.

7.
Sci Total Environ ; 760: 143938, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333400

RESUMO

Environmental issues triggered by increasing nitrate in agricultural river has become global concern. Identifying nitrate sources and transformation are crucial for water sources protection and eliminating nitrate contamination in an agricultural watershed. In this study, chemical and dual isotopic compositions of nitrate were employed to trace the nitrate sources and transformation processes, and proportional contribution of NO3- source were estimated by SIAR based on Bayesian model. NH4+ concentrations in middle Mun and lower Mun in wet season were significantly higher than NO3-, suggesting enhanced runoff processes by flood promote agricultural fertilized NH4+ leaching into the river. Higher Cl- concentration and NO3-/Cl- indicated that manure and sewage was the dominate nitrate source in the Lam Takhong River and the upper Mun. The overall values of δ15N-NO3- and δ18O-NO3- ranged from -3.9‰ to +16.6‰ and from -5.2‰ to +40.0‰, respectively. The results of nitrate isotopes indicated that NO3- mainly originated from soil N nitrogen, chemical fertilizer, and manure and sewage wastes. Spatially, soil N and chemical fertilizer contributed the most nitrate in the mainstream of lower Mun, middle Mun, and the Lam Takhong River; whereas over 60% of nitrate was derived from manure and sewage in the upper Mun. The spatial variation of water discharge and rainfall, together with the nitrate concentration and isotopes inferred that the nitrate sources and transformations in rain-fed river in tropical zone were distinguished from other rivers. High water discharge driven by rainfall events accelerated the nitrate export and the contribution of atmospheric deposition in wet season, and enlarged the contribution of manure and sewage in dry season. This study provided an example for further researches and approaches to assess the effects of tropical climate and agriculture on nitrate accumulation in watershed.

8.
Ann Transl Med ; 8(20): 1292, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209872

RESUMO

Background: The optimal treatment modality for patients with stage IA (T1N0M0) small-cell lung cancer (SCLC) is still unclear. Methods: Patients who received surgical resection or chemo-radiotherapy (CRT) between January 2004 and December 2014 were identified from The Surveillance, Epidemiology and End Results (SEER) database. Surgical resection included lobectomy, wedge resection, segmentectomy with lymphadenectomy [examined lymph node (ELN) ≥1]. Propensity score match analysis was utilized to balance the baseline characteristics. Results: A total of 686 stage IA SCLC cases were included: 337 patients underwent surgery and 349 patients were treated by CRT alone. Surgery achieved a better outcome than CRT alone, with an adjusted hazard ratio (HR) of 0.495. Patients who underwent lobectomy demonstrated a longer overall survival (OS), compared to those who received sublobectomy (crude cohort, median OS, 69 vs. 38 months; match cohort, median OS, 67 vs. 38 months). Patients with ELN >7 presented with longer OS than those with ELN ≤7 (crude cohort, median OS, 91 vs. 49 months; matched cohort, median OS, 91 vs. 54 months). The additional efficacy of chemotherapy or radiotherapy in patients receiving lobectomy was observed. The best prognosis was achieved in the lobectomy plus CRT cohort, with a 5-year survival rate of 73.5%. Conclusions: The prolonged survival associated with lobectomy and chemotherapy or radiotherapy presents a viable treatment option in the management of patients with stage IA SCLC.

9.
Ann Surg Oncol ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33073346

RESUMO

BACKGROUND: The impact of the number of examined lymph nodes (ELNs) on stage correction and prognostication in patients with esophageal squamous cell carcinoma (ESCC) who underwent right transthoracic esophagectomy is still unclear. METHODS: Patients with ESCC who underwent right transthoracic esophagectomy at Sun Yat-sen University Cancer Center between January 1997 and December 2013 were retrospectively enrolled. The Cox proportional hazards regression model was used to determine the effect of ELN count on overall survival. The impact of ELN count on stage correction was evaluated using the hypergeometric distribution and Bayes theorem and ß-binomial distribution estimation, respectively. The threshold of ELNs was determined using the LOWESS smoother and piecewise linear regression. RESULTS: Among the 875 included patients, greater ELNs were associated with a higher rate of nodal metastasis. Significant association between staging bias and the number of ELNs is only observed through the Bayes method. The ELN count did not impact 90-day mortality but significantly impacted long-term survival (adjusted hazard ratio [aHR] 0.986), especially in those patients with node-negative disease (aHR 0.972). In patients with node-negative disease, cut-point analysis showed a threshold ELN count of 21. CONCLUSIONS: A greater number of ELNs is associated with more accurate node staging and better long-term survival in resected ESCC patients. We recommended harvesting at least 21 LNs to acquire accurate staging and long-term survival information for patients with declared node-negative disease using the right thoracic approach.

10.
Cell Transplant ; 29: 963689720963936, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33028108

RESUMO

We have previously reported that miR-9 promotes the homing, proliferation, and angiogenesis of endothelial progenitor cells (EPCs) by targeting transient receptor potential melastatin 7 via the AKT autophagy pathway. In this way, miR-9 promotes thrombolysis and recanalization following deep vein thrombosis (DVT). However, the influence of miR-9 on messenger RNA (mRNA) expression profiles of EPCs remains unclear. The current study comprises a comprehensive exploration of the mechanisms underlying the miR-9-regulated angiogenesis of EPCs and highlights potential treatment strategies for DVT. We performed RNA sequence analysis, which revealed that 4068 mRNAs were differentially expressed between EPCs overexpressing miR-9 and the negative control group, of which 1894 were upregulated and 2174 were downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these mRNAs were mainly involved in regulating cell proliferation/migration processes/pathways and the autophagy pathway, both of which represent potential EPC-based treatment strategies for DVT. Reverse transcriptase quantitative polymerase chain reaction confirmed the changes in mRNA expression related to EPC angiogenesis, migration, and autophagy. We also demonstrate that miR-9 promotes EPC migration and angiogenesis by regulating FGF5 directly or indirectly. In summary, miR-9 enhances the expression of VEGFA, FGF5, FGF12, MMP2, MMP7, MMP10, MMP11, MMP24, and ATG7, which influences EPC migration, angiogenesis, and autophagy. We provide a comprehensive evaluation of the miR-9-regulated mRNA expression in EPCs and highlight potential targets for the development of new therapeutic interventions for DVT.

11.
Vascular ; : 1708538120953668, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33035151

RESUMO

OBJECTIVE: This study aims to investigate the mechanism of transforming growth factor-ß1 (TGF-ß1) in promoting angiogenesis through endothelial-to-mesenchymal transition (EndMT). METHODS: The mesenchymal transition of human umbilical vein endothelial cells (HUVECs) was induced by TGF-ß1. The angiogenesis, migration, and proliferation of HUVECs undergoing EndMT were examined by tube formation assay, scratch assay, Transwell assay, and CCK-8 assay. RESULTS: The outcomes revealed that EndMT promoted angiogenesis, migration, and proliferation of HUVECs and the secretion of the vascular endothelial growth factor (VEGF) of HUVECs. Phosphorylated AKT (p-AKT) increased in EndMT by inhibiting the mitigation of angiogenesis. CONCLUSION: EndMT induces angiogenesis by promoting the secretion of VEGF, and p-AKT participates in this regulation.

12.
Int J Biol Macromol ; 161: 1346-1357, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32784023

RESUMO

In this study, two homogeneous polysaccharides (PFC-1 and PFC-2) having anti-atherosclerotic activity were isolated from Fructus Corni. PFC-1 and PFC-2 were 1,6-α-glucans with the molecular weight of 4.4 kDa and 82.0 kDa, respectively. In the in vitro experiments, PFC-1 and PFC-2 showed significant inhibitory effects on the cholesterol accumulation in RAW264.7 macrophages induced by oxidized low-density lipoproteins (ox-LDL), and the inhibitory rate of PFC-2 was 81.62%. Apolipoprotein E-deficient (ApoE-/-) mice fed high-fat diet (HFD) were used to evaluate the anti-atherosclerotic effects of PFC-2 in vivo. The aortic root lipid area decreased by 55.01% in the PFC-2-administered group as compared to the model group. PFC-2 decreased the levels of serum low-density lipoprotein cholesterol, total cholesterol, triglycerides, and malondialdehyde, increased the superoxide dismutase activity, and reduced the contents of lipid and macrophages in the aortic sinus plaque in ApoE-/- mice fed with HFD. Furthermore, PFC-2 markedly inhibited the expression of type A1 scavenger receptor (SR-A1) and cluster of differentiation 36 (CD36) in ox-LDL-treated macrophages. Taken together, 1,6-α-glucans from Fructus Corni showed significant anti-atherogenic effect, and the mechanism is related to enhanced antioxidant activity of the ApoE-/- mice and down-regulated the expression of SR-A1 and CD36 proteins in macrophages.

13.
J Thorac Dis ; 12(6): 3178-3187, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32642239

RESUMO

Background: Lobectomy has long been regarded as the standard treatment for operable non-small cell lung cancer (NSCLC). Recent studies suggested that segmentectomy could achieve a good prognosis for early-stage NSCLC and might be an alternative to lobectomy in this cohort. Until now, on the issue of comparison between lobectomy and segmentectomy, there remains no published randomized controlled trial (RCT), and all existing evidence is low. Recently, a categorization of lower-level evidence has been proposed, namely, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The aim of this meta-analysis is to compare the oncologic outcome between lobectomy and segmentectomy in NSCLC with the clinical T1N0M0 stage according to the GRADE system. Methods: PubMed, the PMC database, EMBASE, Web of Science, and the Cochrane library were searched prior to May 2019 to identify studies that compared the prognosis between lobectomy and segmentectomy for clinical T1N0M0 NSCLC. The evidence level of the included studies was assessed according to the GRADE system, including level IIA, probably not confounded nonrandomized comparison; level IIB, possibly confounded nonrandomized comparison; and level IIC, probably confounded nonrandomized comparison. The predefined outcomes included overall survival (OS) and disease-free survival (DFS). Univariable and multivariable hazard ratios (HRs) with 95% confidence intervals (95% CI) were pooled using a random-effects model. Results: Twelve nonrandomized studies involving 8,072 participants were included. Of these studies, two were classified as IIA level (16.7%), six as IIB level (50.0%), and four as IIC level (33.3%). When crude HRs were included, compared with lobectomy, segmentectomy was associated with shorter OS but comparable DFS in the entire cohort (OS, pooled HR =1.45, 95% CI, 1.23 to 1.67; DFS, pooled HR =1.03, 95% CI, 0.65 to 1.82) and in patients with nodules ≤2 cm (OS, pooled HR =1.55, 95% CI, 1.33 to 1.80; DFS, pooled HR =0.98, 95% CI, 0.55 to 1.77). When adjusted HRs were included, the impact of segmentectomy on OS and DFS was comparable to that of lobectomy in the entire cohort (OS, pooled HR =1.39, 95% CI, 0.92 to 2.10; DFS, pooled HR =0.83, 95% CI, 0.66 to 1.03) and in patients with nodules ≤2 cm (OS, pooled HR =1.61, 95% CI, 0.87 to 3.00; DFS, pooled HR =0.90, 95% CI, 0.63 to 1.27). Conclusions: Based on our results, although shorter OS is observed in patients received segmentectomy, it is necessary to wait for more results from RCT to draw a valid conclusion.

14.
J Endovasc Ther ; 27(3): 385-393, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32517556

RESUMO

Purpose: To summarize the experience and outcomes of total endovascular repair of thoracoabdominal aortic disease using 3-dimensional (3D) printed models to guide on-site creation of fenestrations in aortic stent-grafts. Materials and Methods: From April 2018 to March 2019, 34 patients (mean age 58±14 years; 24 men) with thoracoabdominal aortic disease were treated in our department. Nineteen patients had thoracoabdominal aortic dissection and 15 had thoracoabdominal aortic aneurysm. Preoperatively, a 3D printed model of the aorta was made according to computed tomography images. In the operating room, the main aortic stent-graft was completely released in the 3D printed model, and the position of each fenestration or branch was marked on the stent-graft. The fenestrations were then made using an electric pen. Wires were sewn to the edge of the fenestrations using nonabsorbable sutures. After customization, the aortic stent-graft was reloaded into the delivery sheath and deployed. Results: The printing process took ~5 hours (1 hour for image reconstruction, 3 hours for printing, and 1 hour for postprocessing). The physician-modified stent-grafts had a total of 107 fenestrations secured by 102 bridging stent-grafts, including 73 covered stents and 29 bare stents. The average procedure time was 5.6±1.2 hours, including a mean 1.3 hours for stent-graft customization. No renal insufficiency or paraplegia occurred. Two branch arteries were lost during the operation. One patient (3%) died 1 week after surgery from a retrograde dissection rupture. One patient developed a minor cerebral infarction postoperatively. The mean follow-up time was 8.5 months. There was 1 endoleak from a fenestration (coil embolized) and 4 distal ruptures of the aortic dissection (3 treated and 1 observed). Conclusion: Three-dimensional printing can be used to guide creation of fenestrated stent-grafts for the treatment of thoracoabdominal aortic diseases involving crucial branches. This technique appears to be more accurate than the traditional measurement method, with short-term follow-up demonstrating the safety and reliability of the method. However, further research and development are needed.


Assuntos
Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Desenho Assistido por Computador , Procedimentos Endovasculares/instrumentação , Impressão Tridimensional , Desenho de Prótese , Stents , Adulto , Idoso , Aneurisma Dissecante/diagnóstico por imagem , Aneurisma Dissecante/fisiopatologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/fisiopatologia , Aortografia , Implante de Prótese Vascular/efeitos adversos , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Anatômicos , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Fluxo de Trabalho
15.
Carbohydr Polym ; 241: 116279, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32507223

RESUMO

Galectin-3 (Gal-3) is a potential target for acute myeloid leukemia therapeutics which contains a carbohydrate-recognition domain. However, the development of polysaccharide inhibitors against Gal-3 is insufficient. In this research, we found a polysaccharide from Angelica sinensis (Oliv.) Diels, named APS-2I, that can bind to Gal-3 with dissociation constant (Kd) of 9.35 ±â€¯0.3 µM and activate the intrinsic apoptosis pathways to induce leukemia cells apoptosis. APS-2I is a homogeneous polysaccharide with a molecular weight of 7.2 × 105 Da, that composes of mannose, rhamnose, galacturonic acid, glucose, galactose and arabinose with a ratio of 4:5:1:10:23:39. In addition, a galactosidase digested fraction of APS-2I named G-4 showed higher affinity to Gal-3 with the Kd of 1.97 ±â€¯0.7 µM and higher apoptosis inducing effect on leukemia cells, which demonstrated that G-4 contains the bio-active structural region of APS-2I. This study provides effective basis for structural analysis and the anti-leukemia mechanism of Angelica polysaccharide APS-2I.

16.
J Cardiovasc Pharmacol ; 76(2): 197-206, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32433359

RESUMO

Previous studies have shown that melatonin (Mel) can effectively ameliorate myocardial ischemia/reperfusion (MI/R) injury, but the mechanism is yet to be fully elucidated. Mel receptors are expressed in the paraventricular nucleus (PVN), which is also involved in regulating cardiac sympathetic nerve activity. The aim of this study was to examine whether Mel receptors in the PVN are involved in the protective effects of Mel against MI/R injury. The results of quantitative polymerase chain reaction, western blot, and immunofluorescence assays indicated that Mel receptor 2 (MT2) expression in the PVN was upregulated after MI/R. Intraperitoneal administration of Mel significantly improved post-MI/R cardiac function and reduced the infarct size, whereas shRNA silencing of MT2 in the PVN partially blocked this effect. Intraperitoneal administration of Mel reduced sympathetic nerve overexcitation caused by MI/R, whereas shRNA silencing of MT2 in the PVN partially diminished this effect. Furthermore, enzyme-linked immunosorbent assay and western blot results indicated that intraperitoneal administration of Mel lowered the levels of inflammatory cytokines in the PVN after MI/R injury, whereas the application of sh-MT2 in the PVN reduced this effect of Mel. Mel significantly reduced the levels of NF-κB after astrocyte oxygen and glucose deprivation/reoxygenation injury, and this effect was offset when MT2 was silenced. The above experimental results suggest that MT2 in the PVN partially mediated the protective effects of Mel against MI/R injury, and its underlying mechanisms may be related to postactivation amelioration of PVN inflammation and reduction of cardiac sympathetic nerve overexcitation.

17.
Eur J Surg Oncol ; 46(10 Pt A): 1956-1962, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32439262

RESUMO

BACKGROUND: The impact of the number of examined lymph nodes (ELNs) on stage correction and prognostication in patients with oesophageal squamous cell carcinoma (ESCC) who underwent left transthoracic oesophagectomy is still unclear. METHODS: Patients with ESCC who underwent left transthoracic oesophagectomy at Sun Yat-sen University Cancer Center between January 1997 and December 2013 were retrospectively enrolled. The Cox proportional hazards regression model was used to determine the effect of ELN count on overall survival (OS). The association between ELN count and nodal status was investigated through scatter plot and binary logistic regression analyses. The impact of ELN count on stage correction was evaluated using the hypergeometric distribution and Bayes theorem. The threshold of ELNs was determined using the LOWESS smoother and piecewise linear regression. RESULTS: Among the 1826 included patients, greater ELNs were associated with a higher rate of nodal metastasis (adjusted OR = 1.018). When the ELN count increased, the omission rate of positive lymph nodes (LNs) decreased. The ELN count did not impact 90-day mortality but significantly impacted long-term survival (adjusted HR = 0.983), especially in those with node-negative disease (adjust HR = 0.972). In patients with node-negative disease, cut point analysis showed a threshold ELN count of 18. CONCLUSIONS: A greater number of ELNs is associated with more accurate node staging and better long-term survival in resected ESCC patients. We recommended harvesting at least 18 LNs to acquire accurate staging and long-term survival information for patients with declared node-negative disease in the left thoracic approach.

18.
BMC Ophthalmol ; 20(1): 152, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295547

RESUMO

BACKGROUND: Myopic eyes are longer than nonmyopic eyes and have thinner choroids. The purpose of present study was to investigate whether a thinner subfoveal choroid at 11 years of age predicted axial eye elongation and myopia during adolescence. METHODS: Longitudinal, population-based observational study. Axial length was measured using an interferometric device and choroidal thickness was measured by spectral-domain optical coherence tomography. Myopia was defined as non-cycloplegic subjective spherical equivalent refraction ≤ - 0.50 diopters. RESULTS: Right eyes of 714 children (317 boys) were examined at age (median (IQR)) 11.5 (0.6) years and 16.6 (0.3) years during which axial length (median (IQR)) increased by 243 (202) µm in eyes without myopia (n = 630) at baseline compared with 454 (549) µm in eyes with myopia (n = 84) at baseline, p < 0.0001. A thicker baseline subfoveal choroid was associated with increased five-year axial elongation after adjustment for baseline axial length in nonmyopic eyes (ß = 27 µm/100 µm, 95%CI 6 to 48, p = 0.011) but not in myopic eyes (p = 0.34). Subfoveal choroidal thickness at 11 years of age did not predict incident myopia at 16 years of age (p = 0.11). Longer baseline axial length was associated with greater five-year axial elongation in both myopic (ß = 196 µm/mm, 95%CI 127 to 265, p < 0.0001) and nonmyopic eyes (ß = 28 µm/mm, 95%CI 7 to 49, p = 0.0085) and the odds for incident myopia increased with 1.57 (95%CI 1.18 to 2.09, p = 0.0020) per mm longer axial length at baseline. CONCLUSION: A thin subfoveal choroid at age 11 years did not predict axial eye elongation and incident myopia from age 11 to 16 years. A longer eye at age 11 years was associated with greater subsequent axial eye elongation and with increased risk of incident myopia at age 16 years.

19.
Aging (Albany NY) ; 12(5): 4506-4526, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32156832

RESUMO

Long non-coding RNAs (lncRNAs) play an essential role in multitudinous physiological and pathological processes, including vascular disease. We previously showed that lncRNA GUSBP5-AS (enst00000511042) is upregulated in endothelial progenitor cells (EPCs) of deep veni thrombosis (DVT) patients. Here, we investigate the role and mechanism of GUSBP5-AS in EPCs and DVT. Using the DVT model, we found that GUSBP5-AS significantly reduced the thrombus size and weight and enhanced the homing ability of EPC to DVT sites to promote resolution and recanalization of thrombus. GUSBP5-AS promoted cell cycle progression, proliferation, migration and invasion in EPCs, enhanced EPC angiogenesis in vitro and in vivo, and inhibited apoptosis. Strikingly, this study showed that GUSBP5-AS was unbalanced and modulated Forkhead Box Protein O1 (FOXO1) in EPCs in patients with DVT by interacting with miR-223-3p. Mechanistically, GUSBP5-AS functions as a sponge of miR-223-3p, which targets FOXO1. Both GUSBP5-AS knockdown and miR-223-3p overexpression remarkably inhibited angiogenesis, migration and invasion in EPCs. Additionally, our data suggested that GUSBP-AS activated the Akt pathway and enhanced fibroblast growth factor 2 (FGF2), matrix metalloproteinase-2/9 (MMP2/9) and F-actin expression. Taken together, this study indicates that GUSBP5-AS modulates angiogenesis, proliferation and homing ability of EPCs via regulating FGF2 and MMP2/9 expression through the miR-223-3p/FOXO1/Akt pathway, which may provide a new direction for the development of DVT therapeutics.

20.
Eur J Med Chem ; 193: 112203, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32197150

RESUMO

Here, we have synthesized and characterized a novel activatable photosensitizer (PS) 8a in which two well-designed boron dipyrromethene (BODIPY) derivatives are utilized as the photosensitizing fluorophore and quencher respectively, which are connected by a disulfide linker via two successive Cu (І) catalyzed click reactions. The fluorescence emission and singlet oxygen production of 8a are suppressed via intramolecular fluorescence resonance energy transfer (FRET) from the excited BODIPY-based PS part to quencher unit, but both of them can be simultaneously switched on by cancer-related biothiol glutathione (GSH) in phosphate buffered saline (PBS) solution with 0.05% Tween 80 as a result of cleavage of disulfide. Also, 8a exhibits a bright fluorescence image and a substantial ROS production in A549 human lung adenocarcinoma, HeLa human cervical carcinoma and H22 mouse hepatoma cells having a relatively high concentration of GSH, thereby leading to a significant photocytotoxicity, with IC50 values as low as 0.44 µM, 0.67 µM and 0.48 µM, respectively. In addition, the photosensitizer can be effectively activated and imaged in H22 transplanted hepatoma tumors of mice and shows a strong inhibition on tumor growth. All these results suggest that such a GSH-responsive photosensitizer based on FRET mechanism may provide a new strategy for tumor-targeted and fluorescence imaging-guided cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Transferência Ressonante de Energia de Fluorescência , Glutationa/química , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfobilinogênio/análogos & derivados , Porfobilinogênio/síntese química , Porfobilinogênio/química , Porfobilinogênio/farmacologia , Relação Estrutura-Atividade
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