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1.
Semin Thromb Hemost ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31627217

RESUMO

Defibrotide has been approved in several geographic jurisdictions for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) for years. However, available data on efficacy and safety for its use in VOD are contrasting. We performed a meta-analysis to evaluate the efficacy and safety of defibrotide in the treatment of hepatic VOD/SOS post-hematopoietic stem cell transplantation (HSCT). PubMed and Embase were searched for studies regarding the efficacy and safety of defibrotide in VOD patients. Survival rate at day + 100 post-HSCT (D + 100 SR), as well as the prognosis, comprising complete response (CR), adverse events including ≥1 adverse event (≥1 AE), hemorrhage, and serious adverse events (SAEs), were pooled using a random effect model. Sixteen studies involving 3,002 participants were included. Pooled estimates for overall D + 100 SR as well as rate of CR, ≥1 AE, hemorrhage, SAEs in VOD patients post-HSCT were 58% (95% CI: 54-62%), 57% (95% CI: 45-68%), 65% (95% CI: 54-75%), 16% (95% CI: 5-27%), 53% (95% CI: 51-55%), respectively, and were 44% (95% CI: 39-48%), 39% (95% CI: 28-50%), 88% (95% CI: 71-100%), 42% (95% CI: 30-55%), 58% (95% CI: 52-64%), respectively, in severe VOD (sVOD) patients. Hemorrhage and hypotension were the most common AEs. Current evidence suggests that defibrotide improves the D + 100 SR and CR in VOD/sVOD patients following HSCT. However, the results of this review/meta-analysis were mainly based on data from observational studies, potentially subject to selection bias. Consequently, higher quality randomized control trials and larger prospective cohort studies are warranted.

2.
Eur J Med Chem ; 183: 111709, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31581004

RESUMO

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (-)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC50 values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (-)-4i induced cell apoptosis and reduced phosphorylation of EGFR and AKT in a dose-dependent manner. Furthermore, (-)-4i exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUC0-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t1/2 = 1.12 h) of (-)-4i displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (-)-4i in vivo resulted in a significant reduction of the tumor volume (TGI: 94.30%). Altogether, these results suggest that (-)-4i warrants further investigation in Non-Small cell lung cancer (NSCLC) therapy.

3.
Nanoscale ; 11(39): 18150-18158, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31556428

RESUMO

Concentration quenching of rare-earth doped upconversion nanoparticles severely limits the dopant concentration, and this greatly hinders their potential applications. Therefore, it is necessary to understand the roles of dopant concentration in photon population and luminescence quenching for materials designed with improved upconversion luminescence (UCL). Herein, the excited-state dynamics of well-accepted NaYF4:Yb3+,Er3+ nanocrystals were investigated as models based on the Kohlrausch-function. The use of the Kohlrausch-function successfully disentangled the rise and decay of dynamics data and well revealed the kinetics. Photon population and concentration quenching mechanisms depending on the sensitizer concentration are deeply revealed by the regular variations of the fitting parameters. The results indicated that high doping of sensitizers will accelerate the population of both green and red emitting energy levels, but cause significant concentration quenching in green emission and little quenching in red emission. Our work opened up new pathways of kinetics analysis, which is beneficial for further mechanism development, and established detailed photon population and concentration quenching models depending on the doping concentration of the sensitizer.

4.
Cancer Chemother Pharmacol ; 84(6): 1209-1218, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31529206

RESUMO

PURPOSE: MicroRNA-519 (miR-519) has been previously reported to function as a tumor suppressor in several types of malignancies. This study aimed to probe the biological role of miR-519 in esophageal squamous cell carcinoma (ESCC). METHODS: qRT-PCR was utilized to test the miR-519 expression level in ESCC tissues and cells. Clinical value of miR-519 was investigated by Kaplan-Meier method. Function assays were conducted to determine the role of miR-519 in radioresistance of ESCC cells. The miR-519-regulated pathways were determined by Kyoto Encyclopedia of Genes and Genomes pathway analysis. RESULTS: Low expression level of miR-519 was closely correlated with the poor prognosis for overall survival of ESCC patients or patients who received radiotherapy. Functional assays indicated that upregulation of miR-519 made ESCC cells more sensitive to γ-ray radiation and facilitated ESCC cell apoptosis triggered by irradiation treatment via regulating DNA response. Ectopic expression of miR-519 decreased the level of p-AKT and p-mTOR, thus inactivating PI3K/AKT/mTOR signaling pathway after irradiation. CONCLUSION: These observations elucidated that upregulated miR-519 is closely correlated with the radiosensitivity of ESCC cells, which may contribute to finding a new promising target for improving the efficiency of radiotherapy in patients with ESCC.

5.
Scand J Immunol ; : e12823, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489646

RESUMO

Sepsis is associated with significant mortality. Early diagnosis and prognosis of patients with sepsis is still a difficult clinical challenge. In this study, the ability of plasma PTX3 (pentraxin 3), MCP1 (monocyte chemoattractant protein 1) and Ang (angiopoietin)1/2 was investigated to evaluate the severity of sepsis. Blood samples were obtained from 43 patients with sepsis. A total of 33 post-surgery patients with infections and 25 healthy individuals served as controls. The results showed that plasma PTX3, MCP1 and Ang2 significantly increased in patients on the first day of septic shock onset, while sepsis patients had significantly higher Ang2 level, compared with controls. Furthermore, PTX3, MCP1 and Ang2 had high AUROC values in patients with septic shock on the first day of sepsis onset. The findings suggest that PTX3, MCP1 and Ang2 maybe early predictors to evaluate the severity of sepsis and septic shock with the latest Sepsis 3.0 definitions.

6.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(7): 852-856, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31441409

RESUMO

OBJECTIVE: To evaluate an effective and feasible quantitative evaluation table of traditional Chinese medicine (TCM) syndrome differentiation, and to observe the effect of combination of TCM syndrome differentiation and standard bundle therapy in patients with septic shock. METHODS: A prospective randomized controlled trial was conducted. The septic shock patients with acute deficiency syndrome admitted to department of critical care medicine of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from January 1st, 2016 to December 31st, 2017 were enrolled. The patients were randomly divided into control group and Shenfu group. The patients in both groups received early application of standardized bundle therapy; those in Shenfu group received 60 mL Shenfu injection infusion in addition for 7 days. The TCM syndrome score was evaluated by classification and scoring method of TCM symptoms. The circulation and tissue perfusion, severity of disease, organ function, inflammation response, adjuvant treatment and 28-day mortality were compared between the two groups. RESULTS: A total of 50 patients with septic shock were enrolled in the analysis, 25 in control group and 25 in Shenfu group. The markedly effective rate of TCM symptoms score in Shenfu group was significantly higher than that in control group [60.0% (15/25) vs. 16.0% (4/25), P < 0.01]. There was no significant difference in all parameters before treatment between the two groups. After treatment, the observation indexes of both groups were improved. Compared with control group, the mean arterial pressure (MAP) in Shenfu group increased more significantly [mmHg (1 mmHg = 0.133 kPa): 13.0 (2.5, 28.5) vs. 6.0 (0, 13.5)], the lactate (Lac) and procalcitonin (PCT) decreased more significantly [Lac (mmol/L): 0.8 (0.1, 3.7) vs. 0.5 (-0.6, 1.7), PCT (µg/L): 2.0 (0.7, 32.3) vs. 0 (-1.8, 3.8)], activated partial thromboplastin time (APTT) was shortened more significantly [s: 8.5 (0, 12.9) vs. 0 (-7.2, 10.0)], and interleukins (IL-2 receptor and IL-6) levels decreased more significantly [IL-2 receptor (ng/L): 1 031.0 (533.0, 1 840.0) vs. 525.5 (186.0, 1 166.8), IL-6 (ng/L): 153.1 (21.4, 406.8) vs. 35.1 (16.3, 110.1)] with significant differences (all P < 0.05). There was no significant difference in the use time of vasoactive drugs, duration of mechanical ventilation, severity of the disease or 28-day mortality between the two groups. However, the use time of vasoactive drugs in Shenfu group was shorter than that in control group (days: 5.48±4.81 vs. 8.28±7.83), and the 28-day mortality was decreased [8.0% (2/25) vs. 20.0% (5/25)]. CONCLUSIONS: TCM syndrome score is helpful to evaluate the effect of TCM syndrome differentiation and treatment, and it is effective and feasible in clinical application. Septic shock patients treated with TCM syndrome differentiation and treatment combined with standard bundle therapy were significantly improved in circulation, tissue perfusion, coagulation function and inflammation reaction.


Assuntos
Medicina Tradicional Chinesa , Choque Séptico/terapia , Pressão Arterial , China , Humanos , Estudos Prospectivos
7.
Bioorg Med Chem Lett ; 29(16): 2150-2152, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31281020

RESUMO

A series of tacrine-pyrazolo[3,4-b]pyridine hybrids were synthesised and evaluated as dual cholinesterase (ChE) and phosphodiesterase 4D (PDE4D) inhibitors for the treatment of Alzheimer's disease (AD). Compound 10j, which is tacrine linked with pyrazolo[3,4-b]pyridine moiety by a six-carbon spacer, was the most potent acetylcholinesterase (AChE) with IC50 value of 0.125 µM. Moreover, compound 10j provided a desired balance of AChE and butylcholinesterase (BuChE) and PDE4D inhibition activities, with IC50 value of 0.449 and 0.271 µM, respectively. The above results indicated that this hybrid was a promising dual functional agent for the treatment of AD.

8.
Parasit Vectors ; 12(1): 345, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300011

RESUMO

BACKGROUND: The poultry red mite (PRM), Dermanyssus gallinae, is one of the most economically deleterious threats to laying-hen industry worldwide. Macrocyclic lactones (MLs) have been widely used in control of mites in mammals, but the effects of MLs on PRMs are not well studied. The main objective of the present study was to systematically evaluate the effects of three MLs, i.e. eprinomectin (EPR), moxidectin (MOX) or ivermectin (IVM), on PRMs fed on chicks following oral administration. METHODS: Chicks in treatment groups were orally administrated with EPR, MOX or IVM at a dose of 5.0 mg/kg bodyweight. Chicks in the control group received the carrier solvent without drug. Chicks in each cage were then infested with 200 starved adult D. gallinae. After infestation and feeding for 12 h, engorged mites were collected to evaluate the acaricidal efficacy of the MLs, and its impacts on the reproduction and blood-meal digestion of D. gallinae. RESULTS: MOX, IVM and EPR demonstrated higher acaricidal efficacies post-treatment compared with the control, i.e. 45.60% for MOX, 71.32% for IVM and 100% for EPR on Day 10. MLs did not have significant effects on the blood-meal ingestion of PRMs, but significantly slowed down blood digestion (P < 0.0001). The oviposition rate, egg hatching rate and fecundity of PRMs in treatment groups were remarkably reduced. Among the three MLs, EPR exhibited the highest performance against PRMs, with an oviposition rate of 1.04%, fecundity of 0.33 eggs per mite and a zero egg hatching rate in EPR treated groups. CONCLUSIONS: EPR, MOX or IVM administrated orally to chicks increased the mortality of D. gallinae, significantly slowed down their blood-meal digestion and significantly reduced their reproductive capability which included the oviposition rate, fecundity and egg hatching rate. The present study highlights the potential of MLs in the control of PRMs.


Assuntos
Acaricidas/uso terapêutico , Fertilidade/efeitos dos fármacos , Compostos Macrocíclicos/uso terapêutico , Infestações por Ácaros/veterinária , Ácaros/efeitos dos fármacos , Doenças das Aves Domésticas/tratamento farmacológico , Acaricidas/administração & dosagem , Administração Oral , Animais , Galinhas/parasitologia , Feminino , Lactonas/farmacologia , Compostos Macrocíclicos/administração & dosagem , Infestações por Ácaros/tratamento farmacológico , Ácaros/fisiologia , Doenças das Aves Domésticas/parasitologia
9.
Hum Reprod ; 34(7): 1186-1194, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31194865

RESUMO

STUDY QUESTION: Is there a role for lysine glutarylation (Kglu), a newly identified protein post-translational modification (PTM), in human sperm? SUMMARY ANSWER: Kglu occurs in several proteins located in the tail of human sperm, and it was reduced in asthenozoospermic (A) men and positively correlated with progressive motility of human sperm, indicating its important role in maintaining sperm motility. WHAT IS KNOWN ALREADY: Since mature sperm are almost transcriptionally silent, PTM is regarded as an important pathway in regulating sperm function. However, only phosphorylation has been extensively studied in mature sperm to date. Protein lysine modification (PLM), a hot spot of PTMs, was rarely studied except for a few reports on lysine methylation and acetylation. As a newly identified PLM, Kglu has not been well characterized, especially in mature sperm. STUDY DESIGN, SIZE, DURATION: Sperm samples were obtained from normozoospermic (N) men and A men who visited the reproductive medical center between February 2016 and January 2018. In total, 61 N men and 59 A men were recruited to participate in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Kglu was examined by immunoblotting and immunofluorescence assays using a previously qualified pan-anti-glutaryllysine antibody that recognizes glutaryllysine in a wide range of sequence contexts (both in histones and non-histone substrates) but not the structurally similar malonyllysine and succinyllysine. The immunofluorescence assay was imaged using laser scanning confocal microscopy and super-resolution structured illumination microscopy. Sperm motility parameters were examined by computer-assisted sperm analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Kglu occurs in several proteins (20-150 kDa) located in the tail of human sperm, especially in the middle piece and the latter part of the principal piece. Sperm Kglu was modulated by regulatory systems (enzymes and glutaryl-CoA) similar to those in HeLa cells. The mean level of sperm Kglu was significantly reduced in A men compared with N men (P < 0.001) and was positively correlated with progressive motility (P < 0.001). The sodium glutarate-induced elevation of Kglu levels in A men with lower Kglu levels in sperm significantly improved the progressive motility (P < 0.001). Furthermore, the reduced sperm Kglu levels in A men was accompanied by an increase in sperm glutaryl-CoA dehydrogenase (a regulatory enzyme of Kglu). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although the present study indicated the involvement of sperm Kglu in maintaining progressive motility of human sperm, the underlying mechanism needs to be investigated further. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study provide an insight into the novel role of Kglu in human sperm and suggest that abnormality of sperm PLMs may be one of the causes of asthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S): National Natural Science Foundation of China (81 771 644 to T.L.; 31 671 204 to X.Z. and 81 871 207 to H.C.); National Basic Research Program of China (973 Program, 2015CB943003 to X.Z.); Natural Science Foundation of Jiangxi, China (20171ACB21006 and 20161BAB204167 to T.L.; 20165BCB18001 to X.Z.). The authors have no conflicts of interest to declare.

10.
Proc Natl Acad Sci U S A ; 116(20): 10019-10024, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31036664

RESUMO

The inflammatory prostaglandin E2 (PGE2) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE2 EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2lox/lox mice attenuated brain infiltration of Cd11b+CD45hi macrophages and CD45+Ly6Ghi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreERT2 (ROSACreER);EP2lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2lox/lox mice, unlike EP2-/- mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.

11.
Methods ; 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31051251

RESUMO

Monitoring extracellular pH (pHe) is important for biology understanding, since pHe and its homeostasis are closely relevant to cellular metabolism. Hydrogel-based pHe sensors have attracted significant attention and showed wide application, while they are tedious with significant time-cost operation and reproducibility variations for high-throughput application. Herein, we synthesized two polymers for pHe monitoring which are soluble in water at room temperature with easy operations and high reproducibility among various micro-plate wells for high-throughput analysis. P1 (P(OEGMA-co-MEO2MA-co-pHS)) and P2 (P(OEGMA-co-pHS)) were synthesized via the Reversible Addition Fragmentation Chain Transfer (RAFT) copolymerization of oligo(ethylene glycol) methacrylate (OEGMA), 2-(2'-methoxyethoxy) ethyl methacrylate (MEO2MA) and the pH sensitive fluorescence moiety N-fluoresceinyl methacrylamide (pHS). P1 is soluble in water at room temperature (25 °C) while insoluble at the temperature above 33 °C, indicating its feature of lower critical solution temperature (LCST) at 33 °C. Further P1 showed higher pH sensitivity and photostability than P2 (without LCST property) when used at physiological temperature (37 °C). Thus, P1 was chosen to in-situ monitor the micro-environmental acidification of E. coli, Hela and Ramos cells during their growth, and the metabolism inhibiting activity of a representative antibiotic, ampicillin. Cell concentration-dependent cellular acidification and drug concentration-dependent inhibition of cellular acidification were observed, demonstrating that the LCST polymer (P1) is suitable for real-time cellular acidification monitoring as well as for high-throughput drug screening. This study firstly demonstrated the use of a LCST polymeric sensor for high-throughput screening of antibiotics and investigation of cell metabolism.

12.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1701-1712, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31002870

RESUMO

Exaggerated endothelial pro-inflammatory response is a hallmark in the early stage of sepsis and contributes to the subsequent tissue injury and organ failure. The anti-inflammatory effects of AMP-activated protein kinase (AMPK) activator metformin in sepsis has been revealed. However, the underlying mechanisms remain not fully understood. In the present study, the potential roles of histone deacetylase 5 (HDAC5) and kruppel-like factor 2 (KLF2) in the effects of metformin on endothelial pro-inflammatory responses were investigated. The results showed that metformin pretreatment increased the phosphorylation of HDAC5 at serine 498, leading to the upregulation of KLF2, and eliminated lipopolysaccharide (LPS) and tumor necrosis factor ⍺ (TNF⍺)-induced upregulation of vascular cell adhesion molecule 1 (VCAM1). Furthermore, the adhesion of HL60 leukocytes to endothelial monolayer was effectively inhibited by metformin. In addition, the in vivo data confirmed that AMPK activation attenuated local and systemic inflammation in endotoxic mice induced by LPS via mediating phosphorylating HDAC5 and restoring KLF2 expression. Our findings revealed that AMPK activation-mediated HDAC5 phosphorylation and KLF2 restoration is, at least partially, responsible to the anti-inflammatory effects of metformin in endotoxemia-induced endothelial cells, which has important implications for the future development of interfering therapies of sepsis.

13.
J Cell Biochem ; 120(9): 14562-14572, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31017716

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most prevalent type in esophageal cancers. Despite accumulating achievements in treatments of ESCC, patients still suffer from recurrence because of the treatment failures, one of the reasons for which is radioresistance. Therefore, it is a necessity to explore the molecular mechanism underlying ESCC radioresistance. Long intergenic noncoding RNA 473 (LINC00473) has been reported to be aberrantly expressed in several human malignancies. However, its biological function in radiosensitivity of ESCC remains to be fully understood. This study explored the role of LINC00473 in radiosensitivity of ESCC cells and whether LINC00473 acted as a competing endogenous RNA to realize its modulation on radioresistance. We found that LINC00473 was markedly upregulated in ESCC tissues and cell lines, and its expression was remarkably related to cellular response to irradiation. In addition, knockdown of LINC00473 could sensitize ESCC cells to radiation in vitro. As for the underlying mechanism, we uncovered that there was a mutual inhibition between LINC00473 and miR-374a-5p. Spindlin1 (SPIN1) was verified as a downstream target of miR-374a-5p, and LINC00473 upregulated SPIN1 expression through negatively modulating miR-374a-5p expression. Furthermore, we revealed that SPIN1 could aggravate the radioresistance of ESCC cells. Finally, overexpression of SPIN1 reversed the LINC00473 silencing-enhanced radiosensitivity in ESCC cells. To sum up, we demonstrated that LINC00473 facilitated radioresistance by regulating the miR-374a-5p/SPIN1 axis in ESCC.

14.
Biochem Biophys Res Commun ; 511(3): 566-572, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30824187

RESUMO

Long non-coding RNAs (lncRNAs) are a group of transcripts, which can regulate the progression of esophageal squamous cell carcinoma (ESCC). According to the data of TCGA, Ladybird homeobox 2 antisense RNA 1 (LBX2-AS1) is a highly expressed lncRNA in ESCC samples. Herein, we chose it for further study. Furtherly, dysregulation of LBX2-AS1 was identified in ESCC tissues with metastasis. Loss-of function assays were conducted and revealed that LBX2-AS1 knockdown suppressed ESCC cell migration and epithelial-mesenchymal transition (EMT). Zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger E-box binding homeobox 2 (ZEB2) are two EMT-related transcription factors. Since LBX2-AS1 promoted the EMT progress and simultaneously enhanced the level of ZEB1 and ZEB2, we further investigated whether LBX2-AS1 promoted cell migration and EMT in ESCC by regulating ZEB1 and ZEB2. Mechanism investigations revealed that RNA binding protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) could interact with LBX2-AS1, ZEB1 and ZEB2, simultaneously. The similar function of HNRNPC in regulating migration and EMT process was demonstrated. ZEB1 has been reported as a positive transcriptional regulator of lncRNA. Therefore, further mechanism analysis was made to demonstrate whether ZEB1 could regulate the transcription of LBX2-AS1. Collectively, our data showed that ZEB1-induced upregulation of LBX2-AS1 promoted cell migration and EMT process in ESCC via enhancing the stability of ZEB1 and ZEB2.

15.
Biol Blood Marrow Transplant ; 25(8): 1486-1491, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30871975

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication in patients after hematopoietic stem cell transplantation. The pathogenesis of TA-TMA is still unclear. Previous studies showed that complement activation plays an important role in the development of TA-TMA. However, no data showed which kind of complement component triggers this process. In this study we found that heme oxygenase-1, which could induce decay-accelerating factor (DAF) and inhibit the membrane-attack complex, was significantly decreased in patients with TA-TMA. DAF levels in the TA-TMA group were in line with the levels in the myocardial infarction group but were lower than levels in the healthy, noncomplication, infection, and graft-versus-host disease groups (P < .05). Human umbilical vein endothelial cells (HUVECs) incubated with TA-TMA plasma showed lower DAF levels compared with that incubated with normal human plasma. Notably, treatment with N-acetylcysteine (NAC), a drug against oxidation, increased the level of DAF. NAC could also inhibit complement activation in HUVECs incubated with TA-TMA plasma. Taken together, we propose that NAC represents a new potential therapy for patients facing TA-TMA.

16.
Sci Total Environ ; 658: 324-332, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30579190

RESUMO

A novel Shewanella@graphene core-shell composite material was fabricated following one-step bioreduction of graphene oxide (GO) by Shewanella putrefaciens CN-32. The surface properties and microstructures were characterized by FTIR, TG-DTG, SEM and TEM, which indicate that GO was effectively reduced to rGO and subsequently loaded onto the outer surface of the microbe Shewanella. CLSM was performed to get insight into the growth of the bacteria after core-shell materials formation. The reduction properties of Shewanella@graphene materials were evaluated using nitrobenzene, a representative model pollutant, as an electron acceptor. The reduction efficiency of Shewanella was improved by strengthening the contact among electron donors, electron shuttles and electron acceptors and changed with the proportions of core-shell materials. The optimal proportion of the core-shell material was OD600 = 0.6:GO = 10 mg/L, which was enhanced by the wrapped rGO and improved adsorption capability. The reduction rate was elevated 30% in comparison with pure Shewanella. In addition, the core-shell material exhibited a favorable recycling performance, which can be reused for at least five times. Facile fabrication and enhanced reduction performance of Shewanella@graphene core-shell composite endows this material with considerable potential in environmental remediation.


Assuntos
Poluentes Ambientais/metabolismo , Nitrobenzenos/metabolismo , Shewanella/metabolismo , Biodegradação Ambiental , Poluentes Ambientais/análise , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Modelos Químicos , Nitrobenzenos/análise , Espectroscopia de Infravermelho com Transformada de Fourier
17.
Eur J Med Chem ; 163: 512-526, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553143

RESUMO

Considering the importance of PDE4D inhibition and the modulation of biometals in Alzheimer's disease (AD) therapeutics, we have designed, synthesized and evaluated a series of new clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of AD. In vitro studies demonstrated that some of the molecules processed remarkable inhibitory activity against phosphodiesterase 4D (PDE4D), strong intracellular antioxidant capacity, potent inhibition of metal-induced aggregation of Aß, and potential blood-brain barrier permeability. Compound 7a demonstrated significant improvement in cognitive and spatial memory in an Aß25-35-induce mouse model in Morris water-maze test (MWM). These results indicate that compound 7a is a promising multifunctional candidate that is worthy of further study.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminopiridinas/farmacologia , Benzamidas/farmacologia , Clioquinol/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Desenho de Drogas , Rolipram/farmacologia , Aminopiridinas/síntese química , Animais , Benzamidas/síntese química , Clioquinol/síntese química , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Humanos , Ligantes , Camundongos , Ratos , Rolipram/síntese química
18.
Bioorg Med Chem ; 26(21): 5718-5729, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30385227

RESUMO

A series of hybrids containing the pharmacophores of the histone deacetylase (HDAC) inhibitor, SAHA, and the antioxidant ebselen were designed and synthesized as multi-target-directed ligands against Alzheimer's disease. An in vitro assay indicated that some of these molecules exhibit potent HDAC inhibitory activity and ebselen-related pharmacological effects. Specifically, the optimal compound 7f was found to be a potent HDAC inhibitor (IC50 = 0.037 µM), possessing rapid hydrogen peroxide scavenging activity and glutathione peroxidase-like activity (ν0 = 150.0 µM min-1) and good free oxygen radical absorbance capacity (value of ORAC: 2.2). Furthermore, compound 7f showed significant protective effects against damage induced by H2O2 and the ability to prevent ROS accumulation in PC12 cells.

19.
Sensors (Basel) ; 18(11)2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30400255

RESUMO

New amphiphilic star or multi-arm block copolymers with different structures were synthesized for enabling the use of hydrophobic oxygen probe of platinum (II)-tetrakis (pentafluorophenyl) porphyrin (PtTFPP) for bioanalysis. The amphiphilic star polymers were prepared through the Atom Transfer Radical Polymerization (ATRP) method by using hydrophilic 4-arm polyethylene glycol (4-arm-PEG) as an initiator. Among the five block copolymers, P1 series (P1a, P1b, and P1c) and P3 possess fluorine-containing moieties to improve the oxygen sensitivity with its excellent capacity to dissolve and carry oxygen. A polymer P2 without fluorine units was also synthesized for comparison. The structure-property relationship was investigated. Under nitrogen atmosphere, high quantum efficiency of PtTFPP in fluorine-containing micelles could reach to 22% and long lifetime could reach to 76 µs. One kind of representative PtTFPP-containing micelles was used to detect the respiration of Escherichia coli (E. coli) JM109 and macrophage cell J774A.1 by a high throughput plate reader. In vivo hypoxic imaging of tumor-bearing mice was also achieved successfully. This study demonstrated that using well-designed fluoropolymers to load PtTFPP could achieve high oxygen sensing properties, and long lifetime, showing the great capability for further in vivo sensing and imaging.

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