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1.
Am J Orthod Dentofacial Orthop ; 157(2): 194-204, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32005471

RESUMO

INTRODUCTION: This study aimed to compare the effects of a novel magnetic palatal expansion appliance (MPEA) during the expansion and maintenance period with that of a screw expansion appliance. METHODS: Based on previous research, the MPEA had a reactivation system that was modified for a broader working range and more stable expansion. Thirty-six male beagle dogs were assigned to a magnetic expansion (ME; n = 12), screwed expansion (SE; n = 12) or control (n = 12) group. Half of the dogs from each group were evaluated only during 5 weeks of activation, whereas the rest were evaluated for 5 weeks of activation and 8 additional weeks of retention. Nonmagnetic metal marking implants were implanted on both sides of the midpalatal suture of all dogs. Three-dimensional assessment of treatment and posttreatment dental and skeletal effects were conducted using cone-beam computed tomography. The width of the midpalatal suture, mineralization and deposition rate of bone, and fluorescence integral optical density were calculated during the expansion and retention periods using tetracycline fluorescence labeling. RESULTS: There were increases in the value of all cone-beam computed tomography parameters in the SE and ME groups during the expansion period, and the increase was significantly greater than that of the control group (P <0.01). However, there was no significant difference in the values of any parameters during the retention period. The width of the midline sutures, mineralization and deposition rate of bone, and integral optical density in the 2 experimental groups were significantly higher than those of the control group (P <0.01), and there was no significant difference between the SE and ME groups. After the retention period, the values of all tetracycline fluorescence evaluation parameters of the experimental groups decreased significantly. CONCLUSIONS: The novel MPEA with a reactivation system was able to expand the midpalatal suture effectively. Dental and skeletal expansion effects are similar to those of the screw expansion appliance. Wearing the appliance as a retainer can effectively maintain the expansion effect. The new bone formation rate was accelerated during the expansion process and decreased to normal levels during the retention period.


Assuntos
Fenômenos Magnéticos , Técnica de Expansão Palatina , Animais , Tomografia Computadorizada de Feixe Cônico , Suturas Cranianas , Cães , Masculino , Maxila , Palato , Dente
2.
J Control Release ; 320: 469-483, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31987922

RESUMO

Astrocytes are key stromal components in glioblastoma (GBM) and have complex interactions with the GBM cells (GBC) promoting the survival, progression and therapy resistance of GBM. In this study, we first demonstrated the existence of a reciprocal activation loop mediated by the STAT3/IL-6 signaling between GBC and astrocytes. This loop of reciprocity was found to be initiated by the constitutive activity of STAT3 and downstream expression of IL-6 in the GBC. GBC-derived IL-6 activated STAT3 and thereby upregulated IL-6 expression in the astrocytes. Astrocyte-derived IL-6 acted back on the GBC causing further activation of STAT3 and leading to enhanced downstream events that promote proliferation, migration, invasion and apoptosis resistance of the GBC. Next, we showed that doxorubicin-polyglycerol-nanodiamond conjugates (Nano-DOX), which could be delivered via GBM-associated macrophages, suppressed STAT3 activity in the GBC reducing their IL-6 output to the astrocytes and thereby abolished the astrocytes' feedback activation of the GBC. Moreover, Nano-DOX also suppressed stimulated activation of STAT3 and IL-6 induced by temozolomide, a first-line anti-GBM chemotherapy, resistance to which critically involves STAT3 activation. In conclusion, Nano-DOX could disrupt the STAT3/IL-6-mediated reciprocal activation loop between the GBC and astrocytes. Nano-DOX also provides a novel approach to therapeutic modulation of the GBM microenvironment.

3.
Biomed Res Int ; 2019: 8756563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828141

RESUMO

Background: By weekly monitoring of China's influenza situation, Chinese National Influenza Center observed that the 2017-18 season was predominated by influenza B virus (IBV)/Yamagata. No studies regarding hospitalizations in adults with IBV infections have been performed. We aimed to describe the clinical characteristics of hospitalized patients with IBV infection in northern China. Methods: In this multicenter and retrospective study, we reviewed all consecutive adult patients with confirmed IBV infections at two level A tertiary teaching hospitals in northern China during the 2017-18 influenza season. Patients' clinical and diagnostic findings, as well as administered treatments and mortality data, were analyzed. Results: A total of 573 patients with a confirmed diagnosis of IBV infection were identified, of whom 22 cases were analyzed because of IBV-related hospitalization. Most patients were admitted to the intensive care unit (ICU) and had at least one underlying disease. The total in-hospital mortality was 27.3%. An elevated initial pneumonia severity index score, elevated direct bilirubin values, and lower platelet levels were associated with mortality (p=0.020, 0.013, and 0.049, respectively). The quick development of bilateral diffuse alveolar infiltrates was the most common imaging characteristics, following consolidation and pleural effusion(s). Risk factors such as HIV infection, pregnancy, underlying medical conditions, coinfections, and treatment delays were not associated with mortality. Conclusions: IBV should not be neglected because of its significant mortality. The elderly and patients with comorbidities, such as hypertension, diabetes, and connective tissue diseases, are more likely to have severe IBV-related pneumonia. Higher heart rates, direct bilirubin levels, initial PSI scores, and lower platelet levels are correlated with hospital mortality. Increased uptake in tetravalent influenza vaccine should be very helpful in preventing future cases of IBV hospitalizations.

4.
CNS Neurol Disord Drug Targets ; 18(9): 713-722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31642795

RESUMO

BACKGROUND: Transient Ischemia/Reperfusion (I/R) is the main reason for brain injury and results in disruption of the Blood-Brain Barrier (BBB). It had been reported that BBB injury is one of the main risk factors for early death in patients with cerebral ischemia. Numerous investigations focus on the study of BBB injury which have been carried out. OBJECTIVE: The objective of this study was to investigate the treatment function of the activation of the Hippo/Yes-Associated Protein (YAP) signaling pathway by combined Ischemic Preconditioning (IPC) and resveratrol (RES) before brain Ischemia/Reperfusion (BI/R) improves Blood-Brain Barrier (BBB) disruption in rats. METHODS: Sprague-Dawley (SD) rats were pretreated with 20 mg/kg RES and IPC and then subjected to 2 h of ischemia and 22 h of reperfusion. The cerebral tissues were collected; the cerebral infarct volume was determined; the Evans Blue (EB) level, the brain Water Content (BWC), and apoptosis were assessed; and the expressions of YAP and TAZ were investigated in cerebral tissues. RESULTS: Both IPC and RES preconditioning reduced the cerebral infarct size, improved BBB permeability, lessened apoptosis, and upregulated expressions of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) compared to the Ischemia/Reperfusion (I/R) group, while combined IPC and RES significantly enhanced this action. CONCLUSION: combined ischemic preconditioning and resveratrol improved blood-brain barrier breakdown via Hippo/YAP/TAZ signaling pathway.

5.
Molecules ; 24(19)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581433

RESUMO

In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1'-gem-dimethyl group with the bulkier cyclopentyl ring, and, we also probed the chain's length and terminal carbon substitution with bromo or cyano groups. One of the analogs synthesized namely 6-[1-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl) cyclopentyl] hexanenitrile (AM4346) has very high affinity (Ki = 4.9 nM) for the mouse CB2 receptor (mCB2) and 131-fold selectivity for that target over the rat CB1 (rCB1). The species difference in the affinities of AM4346 between the mouse (m) and the human (h) CB2 receptors is reduced when compared to our first-generation cannabilactones. In the cyclase assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 3.7 ± 1.5 nM, E(max) = 89%). We have also extended our structure-activity relationship (SAR) studies to include biphenyl synthetic intermediates that mimic the structure of the phytocannabinoid cannabinodiol.

6.
Biomed Pharmacother ; 118: 109407, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545290

RESUMO

The purpose of this study was to observe the functions of preconditioning with endoplasmic reticulum stress (ERS) whether alleviated heart ischemia/reperfusion injury (HI/RI) via modulating IRE1/ATF6/RACK1/PERK and PGC-1α expressions in diabetes mellitus (DM) or not. Diabetic rats were pretreated with 0.6 mg/kg tunicamycin (TM, 0.6 mg/kg tunicamycin was administered via intraperitoneal injection 30 minutes prior to the I/R procedures), and then subjected to 45 minutes of ischemia and 3 hours of reperfusion. Blood and myocardial tissues were collected, myocardial pathological injuries were investigated, serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT) levels were measured, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximum rate of left ventricular pressure rise (+dp/dtmax) and maximum rate of left ventricular pressure drop (-dp/dtmax) were evaluated, reactive oxygen species (ROS) and caspase-3 levels were observed, ΔΨm level and ROS expression were measured, and activated transcript factor 6 (ATF6), receptor for activated C kinase 1 (RACK1), PRK-like ER kinase (PERK), glucose regulated protein 78 (GRP78) and peroxisome proliferator-activated receptor γ co-activator 1-α (PGC-1α) expressions were assessed. The TM ameliorated the pathological damages, reduced myocardial oxidative stress damages, restrained apoptosis, and upregulated the expressions of ATF6, RACK1, PERK, GRP78 and PGC-1α compared with those of the ischemia/reperfusion (I/R) group in DM. This study suggested the preconditioning with endoplasmic reticulum stress (TM) strategy that could enhance protection against HI/RI in DM in clinical myocardial diseases.

7.
Angew Chem Int Ed Engl ; 58(43): 15429-15434, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31397530

RESUMO

The molecule (E)-(5-(3-anthracen-9-yl-allylidene)-2,2-dimethyl-[1,3] dioxane-4,6-dione) (E-AYAD) undergoes E→Z photoisomerization. In the solid state, this photoisomerization process can initiate a physical transformation of the crystal that is accompanied by a large volume expansion (ca. 10 times), loss of crystallinity, and growth of large pores. This physical change requires approximately 10 % conversion of the E isomer to the Z isomer and results in a gel-like solid with decreased stiffness that still retains its mechanical integrity. The induced porosity allows the expanding gel to engulf superparamagnetic nanoparticles from the surrounding liquid. The trapped superparamagnetic nanoparticles impart a magnetic susceptibility to the gel, allowing it to be moved by a magnetic field. The photoinduced phase transition, starting with a compact crystalline solid instead of a dilute solution, provides a new route for in situ production of functional porous materials.

8.
Transplant Proc ; 51(8): 2798-2807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351770

RESUMO

PURPOSE: The objective of this research was to survey the therapeutic action of simvastatin (Sim) on intestinal ischemia/reperfusion injury (II/RI) by modulating Omi/HtrA2 signaling pathways. METHODS: Sprague Dawley rats were pretreated with 40 mg/kg Sim and then subjected to 1 hour of ischemia and 3 hours of reperfusion. The blood and intestinal tissues were collected, pathologic injury was observed, the contents of serum tumor necrosis factor-α and interleukin-6 (IL-6) were estimated, and superoxide dismutase, methane dicarboxylic aldehyde, and cysteinyl aspartate specific proteinase-3 (caspase-3) levels, as well as the expressions of Omi/HtrA2 and caspase-3, were measured in the intestinal tissues. RESULTS: Sim preconditioning mitigated the damnification of intestinal tissues by decreasing oxidative stress, inflammatory damage, and apoptosis and downregulating the expression of Omi/HtrA2 compared to the ischemia/reperfusion group, while Sim+Ucf-101 significantly augmented this effect. CONCLUSION: These results suggest that Sim may alleviate intestinal ischemia/reperfusion injury by modulating Omi/HtrA2 signaling pathways.


Assuntos
Anticolesterolemiantes/farmacologia , Serina Peptidase 2 de Requerimento de Alta Temperatura A/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/análise , Caspase 3/metabolismo , Masculino , Proteínas Mitocondriais/metabolismo , Pirimidinonas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Tionas
9.
Photochem Photobiol Sci ; 18(6): 1587-1595, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31089646

RESUMO

Donor-acceptor Stenhouse adducts comprise a new class of reversible photochromic molecules that absorb in the visible and near-infrared spectral regions. Unimolecular photoisomerization reactions are usually assumed to be insensitive to photochrome density, at least up to millimolar concentrations. In this paper, the photoisomerization kinetics of a third-generation donor-acceptor Stenhouse adduct molecule (denoted DASA) are examined over a range of concentrations. DASA switches efficiently at micromolar concentrations in both liquid solution and in polymers, but as the photochrome concentration is increased there is a dramatic inhibition of the photoisomerization. A kinetic study of both the reactant and photoproduct decays at varying concentrations and in different hosts indicates that the forward photoisomerization and the thermal backward reaction can change by factors of 20 or more depending on DASA concentration. Femtosecond transient absorption experiments show that the initial cis → trans step of the isomerization is not affected by concentration. It is hypothesized that long-range coulombic interactions interfere with the ground state electrocyclization stage of the isomerization, which is unique to the DASA family of photochromes. The physical origin of the inhibition of photoswitching at high photochrome concentrations must be understood if the DASA class of molecules is to be used for applications that require high photochrome concentrations, including photomechanical actuation.

10.
Curr Pharm Des ; 25(9): 1030-1039, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113339

RESUMO

The objective of the study was to examine the therapeutic role of combined ischemic preconditioning (IPC) and resveratrol (RES) on brain ischemia/reperfusion injury (BI/RI) by modulating endogenous bone morphogenetic protein-4 (BMP-4)/reactive oxygen species (ROS)/cyclooxygenase-2 (COX-2) in rats. Sprague Dawley (SD) rats were pretreated with 20 mg/kg RES (20 mg/kg RES was administered once a day via intraperitoneal injection 7 days prior to the I/R procedure) and IPC (equal volumes of saline were administered once a day by intraperitoneal injection over 7 days, and the bilateral common carotid arteries were separated for clamp 5 minutes followed by 5 minutes of reperfusion prior to the I/R procedure), and then subjected to 2 hours of ischemia and 22 hours of reperfusion. Blood and cerebral tissues were collected, cerebral pathological injuries and infarct sizes were investigated, serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were measured, the activities of superoxide dismutase (SOD) and ROS were calculated, the contents of methane dicarboxylic aldehyde (MDA), IL-6, TNF-α and hemodynamic change were estimated, and expression levels of b-cell lymphoma-2 (Bcl-2), bcl-2-associated x (Bax), BMP-4 and COX-2 were assessed in cerebral tissues. IPC, RES and a combination of IPC and RES preconditioning ameliorated the pathological damage and infarct sizes, reduced cerebral oxidative stress damage, alleviated inflammatory damage, restrained apoptosis, and downregulated the expression levels of BMP-4 and COX-2 compared with those of the ischemia/reperfusion (I/R) group. This study suggested a combined strategy that could enhance protection against BI/RI in clinical brain disease.

11.
Biomed Pharmacother ; 112: 108736, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970526

RESUMO

INTRODUCTION: The purpose of the experiment was to survey the therapeutic function of resveratrol (RES)-loaded poly(ethylene glycol)-poly(phenylalanine) (PEG-PPhe) on intestinal ischemia/reperfusion injury (II/RI) via the interaction between CSE/H2S and iNOS/NO compared to free RES in diabetic rats. METHODS: Diabetic rats were pretreated with 20 mg/kg of RES or the RES/PEG-PPhe complex and then subjected to 1 h of ischemia and 3 h of reperfusion. Blood and intestines were collected, intestinal pathological injury was estimated, and the contents of body weight, weights of different tissues, blood glucose, serum insulin, HOMA index, serum nitric oxide (NO) and serum sulfureted hydrogen (H2S) were observed. The dry/wet intestine ratios, the activity of superoxide dismutase (SOD); the contents of methane dicarboxylic aldehyde (MDA), glutathione (GSH), H2S, and NO; and the concentrations of inducible nitric oxide synthase (iNOS) and cystathionine-γ-lyase (CSE) were observed in the intestinal tissues. RESULTS: A significant reduction of weights of different tissues, blood glucose, pathological damage, dry/wet ratios, MDA, NO, iNOS expression and a significant increasement of body weight, serum insulin, HOMA index, SOD, GSH, H2S, CSE expression were observed in both treatment groups. However, a greater reduction of weights of different tissues, blood glucose (7.49-13.49 mmol/L for 72 h vs. the control) and pathological damage, iNOS expression, dry/wet ratios (6.14 ± 0.29 vs. 8.51 ± 0.42), MDA (5.01 ± 0.71 nmol vs. 9.98 ± 0.67 nmol), NO (0.52 ± 0.09 µmol vs. 0.99 ± 0.08 µmol in intestinal tissue; 19.29 ± 0.89 µmol vs. 45.23 ± 1.17 µmol in serum) was observed in the RES/PEG-PPhe group relative to the I/R (P < 0.01 for all); a greater increasement of body weight, serum insulin, HOMA index, SOD (39.79±1.78 U vs. 11.84 ± 1.02 U), GSH (31.25 ± 1.19 mg vs. 10.13 ± 0.64 mg), H2S (39.52 ± 1.32 nmol vs. 13.02 ± 1.03 nmol in intestinal tissue; 9.78 ± 0.79 µmol vs. 3.11 ± 0.85 µmol in serum), CSE expression was observed in the RES/PEG-PPhe group relative to the I/R (P < 0.01 for all). In addition, aminoguanidine (AMI, iNOS inhibitor) reduced I/R injury, and dl-propargylglycine (PAG, CSE inhibitor) increased I/R injury. CONCLUSIONS: The interaction between CSE/H2S and the iNOS/NO-mediated resveratrol/poly(ethylene glycol)-poly(phenylalanine) complex alleviates intestinal ischemia/reperfusion injuries in diabetic rats.


Assuntos
Diabetes Mellitus Experimental/complicações , Portadores de Fármacos/química , Intestinos/efeitos dos fármacos , Fenilalanina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Resveratrol/uso terapêutico , Animais , Cistationina gama-Liase/metabolismo , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Sulfeto de Hidrogênio/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fenilalanina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Resveratrol/administração & dosagem
12.
Planta ; 249(5): 1653, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891649

RESUMO

In the third sentence of "SNP calling and SNPLDB assembly" in "Materials and methods" of the published manuscript, four numbers related to the DNA sequencing data are not correct. The error does not affect any results and conclusions of the article. The four incorrect numbers are 1144.56, 110.87, 3.86 and 4.57, while the correct numbers should be 1219.6, 101.1, 4.4 × and 3.7, respectively, and the correct sentence is given below.

13.
Chem Commun (Camb) ; 55(26): 3709-3712, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30775729

RESUMO

Block-like microcrystals composed of cis-dimethyl-2(3-(anthracen-9-yl)allylidene)malonate are grown from aqueous surfactant solutions. A pulse of 405 nm light converts a fraction of molecules to the trans isomer, creating an amorphous mixed layer that peels off the parent crystal. This photoinduced delamination can be repeated multiple times on the same block.

14.
Nanomedicine (Lond) ; 14(3): 335-351, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30676239

RESUMO

AIM: To mechanistically compare the effects of doxorubicin (DOX) and DOX conjugated with nanodiamonds (Nano-DOX) on human glioblastoma cells (GC). MATERIALS & METHODS: GC viablity, proliferation and activation of apoptosis and autophagy was assayed in response to DOX and Nano-DOX. Expression and release of HMGB1 were measured and its role in apoptosis and autophagy probed in response to DOX and Nano-DOX.  Results: DOX induced apoptosis in GC while Nano-DOX induced autophagy. Inhibition of autophagy in Nano-DOX-treated GC promoted apoptosis. DOX suppressed the emission of HMGB1 while Nano-DOX stimulated HMGB1 emission which was attenuated when autophagy was repressed. Blocking of HMGB1 emission mitigated autophagy and enhanced apoptosis in Nano-DOX-treated GC. Exogenously administered HMGB1 promoted autophagy and protected against apoptosis in both Nano-DOX-treated GC and DOX-treated GC. CONCLUSIONS: Nano-DOX is a potent autophagy activator as opposed to DOX as an apoptosis inducer. Nano-DOX initiates a mutual reinforcement loop between autophagy and HMGB1 in GC and thereby protects GC against apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Glioblastoma/metabolismo , Nanodiamantes/química , Animais , Linhagem Celular Tumoral , Proteína HMGB1/farmacologia , Humanos
15.
Int J Nanomedicine ; 14: 339-351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30655667

RESUMO

Background: Hepatic ischemia/reperfusion-induced pancreatic islet injury (HI/RIPII) was an important pathophysiological phenomenon in clinics. In the present study, we observed the effects of phycocyanin on HI/RIPII. However, the half-life of phycocyanin was extremely short and limited its use in vivo. Materials and methods: In order to overcome this shortcoming, poly(ethylene glycol)-b-(poly(l-glutamic acid)-g-polyethylenimine) (PEG-b-(PG-g-PEI)) was synthesized and estimated as a nanocarrier for lengthening delivery of phycocyanin through the abdominal subcutaneous injection in rats. Phycocyanin (isoelectric point=4.3) was encapsulated with PEG-b-(PG-g-PEI) via electrostatic interactions at pH 7.4. Results: In vitro phycocyanin was fast and efficiently encapsulated and showing efficient loading and sustained release. In vivo the anti-HI/RIPII function of phycocyanin/PEG-b-(PG-g-PEI) complex was surveyed in rats using free phycocyanin as the controls, and the results showed that phycocyanin/PEG-b-(PG-g-PEI) complex reduced HI/RIPII property and enlarged islet functionality. Conclusion: These results suggested that PEG-b-(PG-g-PEI) might be treated as a potential phycocyanin nanocarrier.


Assuntos
Ilhotas Pancreáticas/lesões , Ficocianina/uso terapêutico , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Metabolismo Basal , Glicemia/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Insulina/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Malondialdeído/metabolismo , Ficocianina/química , Ficocianina/farmacologia , Polietilenoimina/química , Ácido Poliglutâmico/química , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/sangue , Superóxido Dismutase/metabolismo
16.
Acta Biomater ; 86: 381-394, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30654213

RESUMO

Immunosuppression is a salient feature of GBM associated with the disease's grim prognosis and the limited success of anti-GBM immunotherapy. Stimulating immunogenicity of the GBM cells (GC) is a promising approach to subverting the GBM-associated immunosuppression. We had previously devised a drug composite based on polyglycerol-functionalized nanodiamonds bearing doxorubicin (Nano-DOX) and demonstrated that Nano-DOX effectively modulated GBM's immunosuppressive microenvironment through stimulating the immunogenicity of GC and initiated anti-GBM immune responses. The present study now explored the mechanism of Nano-DOX's immunostimulatory action. Nano-DOX was found to induce autophagy rather than apoptosis in GC and stimulated GC to emit antigens and damage-associated molecular patterns (DAMPs) that are potent adjuvants, which resulted in enhanced activation of dendritic cells (DC). Heightened autophagosome release was observed in Nano-DOX-treated GC but was shown not to be a major channel of antigen donation. Blocking autophagy in GC not only reduced Nano-DOX-stimulated GC antigen donation and DAMPs emission, but also efficiently attenuated DC activation stimulated by Nano-DOX-treated GC. Taken together, these findings suggest that activation of autophagy is a central mechanism whereby Nano-DOX stimulates GC's immunogenicity. Our work provides new insight on how nanotechnology can be applied to therapeutically modulate the GBM immune microenvironment by harnessing autophagy in the cancer cells. STATEMENT OF SIGNIFICANCE: Immunosuppression is a salient feature of GBM associated with the grim prognosis of the disease and the limited success of anti-GBM immunotherapy. We demonstrated that Doxorubicin-polyglycerol-nanodiamond composites could activate autophagy in GBM cells and thereby stimulate the immunogenecity of GBM cells. This discovery 1, sheds new light on how nanotechnology could be applied to therapeutically modulate the tumor immune microenvironment, and 2, provides a powerful tool for subverting the GBM's immunosuppressive microenvironment, which has great therapeutic potential for the treatment of GBM.

17.
Neuron ; 100(5): 1116-1132.e13, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30344043

RESUMO

In the developing brain, immature synapses contain calcium-permeable AMPA glutamate receptors (AMPARs) that are subsequently replaced with GluA2-containing calcium-impermeable AMPARs as synapses stabilize and mature. Here, we show that this essential switch in AMPARs and neuronal synapse maturation is regulated by astrocytes. Using biochemical fractionation of astrocyte-secreted proteins and mass spectrometry, we identified that astrocyte-secreted chordin-like 1 (Chrdl1) is necessary and sufficient to induce mature GluA2-containing synapses to form. This function of Chrdl1 is independent of its role as an antagonist of bone morphogenetic proteins (BMPs). Chrdl1 expression is restricted to cortical astrocytes in vivo, peaking at the time of the AMPAR switch. Chrdl1 knockout (KO) mice display reduced synaptic GluA2 AMPARs, altered kinetics of synaptic events, and enhanced remodeling in an in vivo plasticity assay. Studies have shown that humans with mutations in Chrdl1 display enhanced learning. Thus astrocytes, via the release of Chrdl1, promote GluA2-dependent synapse maturation and thereby limit synaptic plasticity.


Assuntos
Astrócitos/metabolismo , Proteínas do Olho/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal , Receptores de AMPA/metabolismo , Sinapses/fisiologia , Animais , Células Cultivadas , Proteínas do Olho/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Ratos Sprague-Dawley
18.
Biomaterials ; 181: 35-52, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30071380

RESUMO

Glioblastoma (GBM) is the deadliest and most common type of primary brain tumor in adults with a grim prognosis despite multimodal treatments. Dendritic cell (DC)-based immunotherapy has emerged as a promising therapeutic modality for GBM, whose efficacy is nonetheless fundamentally undermined by GBM-induced immunosuppression. Inducing emission of damage associated molecular patterns (DAMPs) is a highly effective strategy to subvert tumor-associated immunosuppression. The present work was carried out to explore the idea of subverting the GBM immunosuppressive microenvironment through DC-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites (Nano-DOX), a potent DAMPs inducer demonstrated by our previous study, and thereby eliciting enhanced DC-driven anti-GBM immune response. In the in-vitro work on human cell models, Nano-DOX-loaded DC were shown to be functionally viable and release cargo drug to co-cultured GBM cells (GC). Nano-DOX-treated GC displayed not only profuse DAMPs emission but also antigen release. Enhanced activation and acquisition and presentation of GC-derived antigen were then demonstrated in DC in co-culture with GC and Nano-DOX. Consistently, co-culture with GC and Nano-DOX also activated mouse bone marrow-derived DC (mDC) which in turn stimulated mouse spleen-derived lymphocytes which ultimately suppressed co-cultured GC. Next, athymic mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mDC and, 48 h later, spleen-derived lymphocytes. The presence of Nano-DOX, DAMPs emission and enhanced infiltration and activation of mDC and lymphocytes were detected in the GBM xenografts. Taken together, our results demonstrate the efficacy of DC-mediated delivery of Nano-DOX to stimulate GC immunogenicity and elicit anti-cancer immune response in the GBM. By this work, we present a novel approach with great application potential to subverting the GBM immunosuppressive microenvironment and to anti-GBM immunotherapy. Investigation has also been conducted probing the mechanisms by which Nano-DOX stimulates GC immunogenicity, which is described in a follow-up paper.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Células Dendríticas/metabolismo , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Glicerol/química , Polímeros/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/química , Feminino , Glioblastoma , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanoestruturas/efeitos adversos , Nanoestruturas/química , Células THP-1
19.
Int J Nanomedicine ; 13: 3625-3640, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983558

RESUMO

Background: Lumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects. Methods and results: Here, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(ε-benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied. Conclusion: We propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits.


Assuntos
Albuminas/uso terapêutico , Endopeptidases/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Albuminas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina B1/metabolismo , Portadores de Fármacos/química , Endopeptidases/sangue , Endopeptidases/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lisina/análogos & derivados , Lisina/síntese química , Lisina/química , Masculino , Microvasos/patologia , Peso Molecular , Paclitaxel/sangue , Paclitaxel/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polilisina/análogos & derivados , Polilisina/síntese química , Polilisina/química , Ratos Sprague-Dawley , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologia
20.
Med Sci Monit ; 24: 4869-4875, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30006502

RESUMO

BACKGROUND The purpose of this study was to investigate whether DEX exerts protective mechanisms in rats with acute lung injury (ALI) induced by the endotoxin lipopolysaccharide (LPS). The mortality rate of ALI is extremely high. DEX, an a2 adrenergic receptor agonist, has potent anti-inflammatory and organ-protective effects in addition to its sedative and analgesic properties. We sought to elucidate whether DEX can attenuate acute lung injury. MATERIAL AND METHODS Forty-eight Wister rats were randomly divided into 4 groups (n=12, per group): the normal saline control (NS) group, receiving tail-vein injection of 0.9% normal saline (5 mL/kg); the LPS (L) group, receiving tail-vein injection of LPS (8 mg/kg); the LPS+DEX (L+D) group, receiving tail-vein injection of LPS (8 mg/kg), 0.5h before treated with DEX (50 ug/kg); and the DEX+LPS (D+L) group, receiving tail-vein injection of LPS (8 mg/kg) 0.5 h after being treated with DEX (50 ug/kg). Then, we measured the wet­to­dry weight ratio of lung tissue, the ALI pathology score, and HE staining of lung tissue, and assessed the Oxygen Tension index. RESULTS The present study revealed that LPS­induced rats exhibited significant lung injury, characterized by the deterioration of histopathology, ALI Pathology Score, wet­to­dry weight ratio, and Oxygen Tension index (MBP, PaO2, PaCO2, PH, HCO3-, and Lac), which were attenuated by DEX treatment. CONCLUSIONS Collectively, the present results demonstrate elucidate the molecular mechanisms by which DEX ameliorates LPS­induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dexmedetomidina/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Endotoxinas , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-Dawley
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