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1.
Heart Lung ; 63: 159-166, 2024.
Article in English | MEDLINE | ID: mdl-37922664

ABSTRACT

INTRODUCTION: It is important to clarify the secretion clearance and lung-related effects of the PEEP-ZEEP maneuver in adults undergoing mechanical ventilation (MV). There is no published comprehensive meta-analysis of the effects of PEEP-ZEEP in adults receiving MV. OBJECTIVES: The aim of this study was to analyze published randomized controlled trials, investigating the effects of the PEEP-ZEEP maneuver in adults undergoing mechanical ventilation. METHODS: We searched Embase, PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from the date of inception of the databases until 6 May 2023. Quality assessment was using the Cochrane Systematic Assessment Handbook. The GRADE system was used to grade the quality of the evidence. RESULTS: A total of 12 trials were included, and the results of the meta-analysis showed that PEEP-ZEEP was not superior to bag squeezing for the removal of bronchial secretions. One study showed a significant increase in the amount of secretion retrieved with the PEEP-ZEEP when compared with tracheal suctioning. Additionally, PEEP-ZEEP was more effective than bag squeezing at improving oxygen saturation. However, one trial showed that bag squeezing was better at improving dynamic compliance. No other differences were found between PEEP-ZEEP and other techniques, except for one study showing more frequent changes in diastolic blood pressure with PEEP-ZEEP compared with ventilator hyperinflation. CONCLUSION: PEEP-ZEEP was not superior to bag squeezing in removing bronchial secretions. However, it improves oxygen saturation when compared to bag squeezing, and no adverse effects on patients' respiratory systems have yet been observed.


Subject(s)
Positive-Pressure Respiration , Respiration, Artificial , Adult , Humans , Respiration, Artificial/methods , Positive-Pressure Respiration/methods , Ventilators, Mechanical , Randomized Controlled Trials as Topic
2.
J Phys Chem Lett ; 15(1): 113-120, 2024 Jan 11.
Article in English | MEDLINE | ID: mdl-38147530

ABSTRACT

Although chirality plays an important role in the natural world, it has also attracted much scientific attention in nanotechnology, in particular, spintronics and bioapplications. Chiral carbon dots (CDs) are promising nanoparticles for sensing and bioimaging since they are biocompatible, ecofriendly, and free from toxic elements. Herein, green and red emissive chiral CDs are fabricated via surface modification treatment of achiral CDs at room temperature. After modification with l-cysteine molecules, the treated CDs demonstrate an intense chiral signal in the region of 200-300 nm with a dissymmetry factor up to 2.3 × 10-4 and high photoluminescence quantum yields of 19% and 15% for green and red emission bands, respectively. These CDs preserve their chiral signal in different ion systems, such as those with pH changes or in the presence of metal ions, along with remarkably low cytotoxicity, making them potential candidates for use as photoluminescent labels for biological objects.


Subject(s)
Nanoparticles , Quantum Dots , Cysteine , Carbon/chemistry , Quantum Dots/chemistry , Ions
3.
J Health Serv Res Policy ; 29(2): 84-91, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38108294

ABSTRACT

OBJECTIVE: Primary health workers (PHWs) are a critical pillar of health systems but primary health care centers often struggle to attract and retain talented staff. To better understand why this is, we investigated the job preference of PHWs in a Chinese urban setting. METHODS: In a discrete choice experiment, PHWs from 15 primary health care centers in Guangzhou, China, made trade-offs between several hypothetical job scenario combinations of salary, type of health institution, bianzhi (permanent post), work years required for promotion, career development and training opportunities, educational opportunities for children, and community respect. Based on the estimate of the mixed logit model, willingness to pay and policy simulations were applied to estimate the utility of each attribute. RESULTS: Data were collected from 446 PHWs. The PHWs were willing to forgo Chinese Renminbi 2806.1 (US$ 438.5) per month to obtain better education opportunities for their children, making it the most important non-monetary factor. Their preferences were also influenced relatively more by salary, bianzhi, and community respect, than with the other attributes we tested for, work years required for promotion, career development and training opportunities, and type of health institution. CONCLUSION: Salary is a robust predictive factor, while three non-monetary factors (opportunities for children's education, bianzhi, and community respect) are essential in retaining health workers in primary care.


Subject(s)
Health Personnel , Salaries and Fringe Benefits , Child , Humans , Health Workforce , China , Surveys and Questionnaires , Primary Health Care , Choice Behavior , Career Choice
4.
Horm Metab Res ; 55(8): 555-562, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37399835

ABSTRACT

This study was designed to assess the role and mechanism of circRNA SCAR in human retinal microvascular endothelial cells (hRMVECs) treated with high glucose. Quantitative real-time polymerase chain reaction (qRT-PCR) and cell counting kit 8 (CCK-8) were used to detect the effects of different concentrations of glucose on circRNA SCAR expression and cell proliferation in hRMVECs. Cell viability, levels of oxygen species (ROS), malondialdehyde (MDA) and adenosine triphosphate (ATP), as well as activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the transfected hRMVECs in each group were detected using CCK-8 and their corresponding detection kits. Changes in mtDNA copy number in high-glucose-induced hRMVECs were observed by qRT-PCR. Additionally, western blot was applied to detect effect of overexpressing circRNA SCAR on the expression levels of mitochondrial function-related proteins (Drp1 and Fis1) and cell permeability-related proteins (claudin-5, occludin and ZO-1) in hRMVECs under high-glucose concentration. According to experimental results, high glucose significantly downregulated circRNA SCAR expression and inhibited cell proliferation in hRMVECs. Instead, overexpression of this circRNA SCAR promoted cell proliferation, reduced levels of ROS, MDA and ATP, and increased SOD and CAT activities in hRMVECs under high-glucose concentration. Also, circRNA SCAR overexpression reversed the high-glucose-induced decrease in mtDNA copy number as well as, high-glucose-induced upregulation of Drp1 and Fis1 protein expression and downregulation of claudin-5, occludin and ZO-1 protein expression in hRMVECs. In summary, circRNA SCAR promotes the proliferation of hRMVECs under high-glucose concentration, alleviates oxidative stress induced by high glucose, and improves mitochondrial function and permeability damage.


Subject(s)
Endothelial Cells , RNA, Circular , Humans , Adenosine Triphosphate/metabolism , Apoptosis , Claudin-5/metabolism , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Endothelial Cells/metabolism , Glucose/metabolism , Mitochondria/metabolism , Occludin/metabolism , Oxidative Stress , Permeability , Reactive Oxygen Species/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , Superoxide Dismutase
5.
Ann Vasc Surg ; 89: 312-321, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36272664

ABSTRACT

BACKGROUND: Deep venous thrombosis (DVT) is one of the major health problems worldwide. Apolipoprotein L domain containing 1 (APOLD1) was reported to be downregulated in DVT. The present study intended to investigate whether APOLD1 affects thrombus formation in a rat model of DVT. METHODS: The rat model of DVT was established by inferior vena cava (IVC) stenosis. At 6 hr, 12 hr, 24 hr, and 48 hr after IVC stenosis, the gross IVC with thrombus was dissected and observed. Then, the rats were preinjected with the lentiviral overexpression vector, APOLD1-LVs, 1 hr before IVC stenosis, to evaluate the influence of APOLD1 on thrombosis in rats. The serum levels of D-dimer and TAT as well as the content of TF in IVC tissues were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: IVC stenosis resulted in thrombus formation in rats, increased serum levels of D-dimer and TAT, and decreased APOLD1 expression. APOLD1 overexpression inhibited in vivo thrombosis, reduced serum levels of D-dimer, and downregulated tissue factor (TF) activity and level. APOLD1 overexpression also increased p-PI3K and p-Akt protein levels. CONCLUSIONS: APOLD1 suppresses thrombus formation in a rat model of DVT via downregulating TF expression by activating the PI3K/Akt pathway.


Subject(s)
Thrombosis , Venous Thrombosis , Rats , Animals , Proto-Oncogene Proteins c-akt , Thromboplastin , Phosphatidylinositol 3-Kinases , Apolipoprotein L1 , Constriction, Pathologic , Treatment Outcome , Vena Cava, Inferior/diagnostic imaging , Vena Cava, Inferior/metabolism
6.
Acta Pharmacol Sin ; 42(12): 1991-2003, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34531546

ABSTRACT

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.


Subject(s)
Benzene Derivatives/therapeutic use , Furans/therapeutic use , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Rotenone/toxicity , alpha-Synuclein/metabolism , Animals , Apoptosis/drug effects , Behavior, Animal/drug effects , Benzene Derivatives/pharmacology , Cathepsin D/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Furans/pharmacology , Humans , Lysosomes/drug effects , Male , Mice, Inbred C57BL , Movement/drug effects , Neuroprotective Agents/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic use , Sirtuin 1/metabolism
7.
Medicine (Baltimore) ; 100(16): e25599, 2021 Apr 23.
Article in English | MEDLINE | ID: mdl-33879723

ABSTRACT

BACKGROUND: The introduction of endovascular surgery has led to frequent stent use, although in-stent restenosis (ISR) remains a challenging issue. Drug-coated balloon (DCB) and conventional balloon angioplasty (BA) are common endovascular procedures for addressing ISR in the femoropopliteal artery. However, there is controversy regarding which procedure provides the greatest benefit to patients. METHODS: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched for prospective controlled trials that compared DCB and BA for patients with ISR in the femoropopliteal artery. The study has been approved by Ethics Committee of Wuhan Central Hospital. RESULTS: The meta-analysis included 6 prospective trials with 541 patients. We found that DCB use was associated with significant reductions in binary restenosis at 6 months (relative risk [RR]: 0.45, 95% confidence interval [CI]: 0.33-0.63; P < .00001), binary restenosis at 1 year (RR: 0.44, 95% CI: 0.34-0.57; P < .00001), target lesion revascularization (TLR) at 6 months (RR: 0.36, 95% CI: 0.20-0.65; P = .0006), and TLR at 1 year (RR: 0.38, 95% CI: 0.27-0.54; P < .00001). The DCB group also had significantly better clinical improvement (RR: 1.39, 95% CI: 1.13-1.71; P = .002), although we did not detect inter-group differences in terms of death, target vessel thrombosis, or ipsilateral amputation. The brand of DCB may a cause of heterogeneity. CONCLUSION: Relative to BA, DCB use increases the durability of treatment for ISR in the femoropopliteal artery, based on significant reductions in binary restenosis and TLR at 6-12 months after the procedure. Furthermore, DCB use was associated with better clinical improvement. However, additional randomized controlled trials are needed to validate these findings.


Subject(s)
Angioplasty, Balloon, Coronary/methods , Coronary Restenosis/surgery , Drug Delivery Systems/methods , Postoperative Complications/surgery , Stents/adverse effects , Aged , Aged, 80 and over , Coronary Restenosis/etiology , Female , Femoral Artery/surgery , Humans , Male , Middle Aged , Popliteal Artery/surgery , Postoperative Complications/etiology , Prospective Studies , Randomized Controlled Trials as Topic , Treatment Outcome
8.
Brain Behav Immun ; 92: 67-77, 2021 02.
Article in English | MEDLINE | ID: mdl-33221489

ABSTRACT

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1ß. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.


Subject(s)
HMGB1 Protein , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Phosphodiesterase 4 Inhibitors , Signal Transduction , Stress, Psychological , Animals , Benzene Derivatives , Cyclic Nucleotide Phosphodiesterases, Type 4 , Depression , Furans , Interleukin-1beta , Mice , Receptor for Advanced Glycation End Products
9.
Sheng Li Xue Bao ; 72(5): 667-676, 2020 Oct 25.
Article in Chinese | MEDLINE | ID: mdl-33106837

ABSTRACT

Sarcopenia is an age-related degenerative disease, in which skeletal muscle mass and function are reduced during aging process. Physical intervention is one of the most effective strategies available for the treatment of sarcopenia. Studies have shown that microRNAs (miRNAs), as important regulators of gene expression, play an important role in maintaining the homeostasis of senescent skeletal muscle cells by regulating skeletal muscle cell development (proliferation and differentiation), mitochondrial biogenesis, protein synthesis and degradation, inflammatory response and metabolic pathways. Furthermore, exercise can combat age-related changes in muscle mass, composition and function, which is associated with the changes in the expression and biological functions of miRNAs in skeletal muscle cells. In this article, we systematically review the regulatory mechanisms of miRNAs in skeletal muscle aging, and discuss the regulatory roles and molecular targets of exercise-mediated miRNAs in muscular atrophy during aging process, which may provide novel insights into the prevention and treatment of sarcopenia.


Subject(s)
MicroRNAs , Sarcopenia , Aging/genetics , Exercise Therapy , Humans , MicroRNAs/genetics , Muscle, Skeletal , Sarcopenia/genetics , Sarcopenia/therapy
10.
Br J Pharmacol ; 177(10): 2333-2350, 2020 05.
Article in English | MEDLINE | ID: mdl-31972868

ABSTRACT

BACKGROUND AND PURPOSE: Roflupram improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of roflupram on Parkinson's disease (PD) remain unknown. Therefore, we aimed to elucidate the pharmacological effects and mechanisms of action of ROF in experimental models of PD. EXPERIMENTAL APPROACH: We used an in vitro PD model of SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium iodide (MPP+ ). Cell viability and apoptosis were analysed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity, and ROS were measured by a mitochondrial tracker, Seahorse Analyzer, and a MitoSOX-Red dye. For in vivo PD model, behavioural tests, Nissl staining, and immunohistochemistry were used to evaluate protection by roflupram. The levels of TH, cAMP response element-binding protein (CREB), and PPARγ coactivator-1α (PGC-1α) were analysed by western blotting. KEY RESULTS: Roflupram decreased MPP+ -induced apoptosis in SH-SY5Y cells and human dopaminergic neurons. Roflupram also increased mitochondrial respiratory capacity, decreased ROS production, and restored mitochondrial morphology. Roflupram reversed the MPP+ -induced reductions of phosphorylated CREB, PGC-1α and TH. These protective effects were blocked by the PKA inhibitor H-89 or by PGC-1α siRNA. In mice treated with MPTP, roflupram significantly improved motor functions. Roflupram prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC-1α in the substantia nigra and striatum. CONCLUSION AND IMPLICATIONS: Roflupram protected dopaminergic neurons from apoptosis via the CREB/PGC-1α pathway in PD models. Hence, roflupram has potential as a protective drug in the treatment of PD.


Subject(s)
Cyclic AMP Response Element-Binding Protein , Parkinson Disease , Animals , Benzene Derivatives , Cell Line, Tumor , Cyclic AMP Response Element-Binding Protein/metabolism , Dopaminergic Neurons/metabolism , Furans , Mice , Mice, Inbred C57BL , Models, Theoretical , Neuroprotection , Parkinson Disease/drug therapy , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
11.
J Nanosci Nanotechnol ; 20(2): 949-956, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-31383091

ABSTRACT

To improve lithium storage performances of Si anode for lithium-ion batteries, Si nanoparticles encapsulated into porous N-doped carbon (Si@PNC) was devised and prepared by metal nitrate accelerated polymer blowing process. The Si@PNC composites have large specific surface area of 221.7 m² g-1 and possess a great deal of mesopores and micropores, which are attributed to the carbonization of PVP and etching metallic nanoparticles. As anode for lithium ion battery, the initial discharge capacity of Si@PNC composites is high to 1626 mA h g-1, and the specific capacity still retains 1030 mA h g-1 after 200 cycles at 200 mA g-1. Meanwhile, remarkably improved rate capability is achieved with an excellent reversible specific capacity of 375 mA h g-1 at 5.0 A g-1. The excellent lithium storage performances benefit from the unique porous core-shell structure of Si@PNC composites, which improve electroconductivity, reduce volume dilatation and accelerate lithium ion transmission.

12.
Phytochem Anal ; 31(2): 242-251, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31435982

ABSTRACT

INTRODUCTION: Ephedrine is a typical compound found in lots of plant species that is used in several medicines for the treatment of asthma and bronchitis. However, excess amounts are harmful to humans, so it needs to be removed. OBJECTIVE: This study developed a multi-phase extraction (MPE) method with a molecular imprinted polymer (MIP) coated ionic liquid (IL)-based silica (SiO2 @IL@MIP) to simultaneously extract and separate ephedrine from Pinellia ternata, 10 medicines, and urine samples. METHODS: IL was immobilized on silica. Subsequently, the IL was combined with the functional monomer, followed by the addition of the crosslinker and template. The resulting sorbent was applied to the MPE, and the extraction, washing and elution solvents were evaluated. RESULTS: Fourier-transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) confirmed the synthesis of SiO2 @IL@MIP. A maximum adsorption amount of 5.76 mg/g was obtained at 30°C at a neutral pH. In MPE, 10.00 mL of methanol could extract all the ephedrine from Pinellia ternata. The interference was removed by washing with 4.00 mL of water, ethanol, and acetonitrile. Finally, 8.00 mL of methanol/acetic acid (99:1, v/v) was applied as the elution solvent. The following were extracted: 5.50 µg/g of ephedrine from Pinellia ternata, 0.00-46.50 µg/g from the 10 herbal medicines, and 68.70-102.80 µg/mL in the urine samples. CONCLUSION: The proposed method was applied successfully to the simultaneously extraction and separation of ephedrine from plants and medicines. These results are expected to provide important data for the development of new methods for the separation and purification of bioactive compounds.


Subject(s)
Ionic Liquids , Molecular Imprinting , Pinellia , Adsorption , Chromatography, High Pressure Liquid , Ephedrine , Herbal Medicine , Humans , Polymers , Silicon Dioxide , Solid Phase Extraction
13.
Free Radic Biol Med ; 135: 87-101, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30818055

ABSTRACT

The etiology of Parkinson's disease (PD) is generally not well understood, but it is believed to involve excessive oxidative insult. Hence, identifying therapeutic targets and compounds that exhibit protective effects against oxidative damage is a reasonable strategy to slow down the progression of PD. FCPR16 is a novel phosphodiesterase 4 inhibitor with little emetic potential. Our previous studies showed that FCPR16 was able to block 1-Methyl-4-phenylpyridine (MPP+)-induced oxidative damage in SH-SY5Y cells and neurons. However, the detailed mechanism of this is unknown. Here, we found that FCPR16 triggered autophagy in SH-SY5Y cells, as evidenced by an increased level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62. Inhibition of autophagy by 3-MA or chloroquine decreased the effect of FCPR16 on the accumulation of autophagic vacuoles and the fluorescence signal of lysosomes. In SH-SY5Y cells treated with MPP+, we found that FCPR16 increased the level of LC3-II, and 3-MA attenuated the protective effect of FCPR16 against MPP+-induced toxicity. Treatment of SH-SY5Y cells with FCPR16 prevented MPP+-induced production of reactive oxygen species (ROS) and the decline of mitochondrial membrane potential (Δψm). Importantly, we also found that FCPR16 phosphorylated and thus activated AMP-activated protein kinase (AMPK) in SH-SY5Y cells treated with MPP+. In contrast, blockade of the AMPK pathway with compound C blocked the role of FCPR16 in autophagy enhancement. Similarly, the roles of FCPR16 in the production of ROS, decline of Δψm, and neuroprotection were blocked by compound C as well. Similar results were consistently obtained in primary cultured neurons. Taken together, these results suggest that FCPR16 is effective in protecting SH-SY5Y cells and neurons against oxidative stress via AMPK-dependent autophagy. Our findings indicate the potential application of FCPR16 in PD treatment.


Subject(s)
Benzamides/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Parkinson Disease/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , AMP-Activated Protein Kinase Kinases , Animals , Autophagy/drug effects , Gene Expression Regulation/drug effects , Humans , Mice , Microtubule-Associated Proteins/genetics , Neurons/drug effects , Neurons/pathology , Neuroprotection/genetics , Oxidative Stress/drug effects , Parkinson Disease/genetics , Parkinson Disease/pathology , Primary Cell Culture , Protein Kinases/genetics , RNA-Binding Proteins/genetics , Reactive Oxygen Species/metabolism
14.
Int J Neuropsychopharmacol ; 22(2): 143-156, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30407503

ABSTRACT

Background: Phosphodiesterase 4 is a promising target for developing novel antidepressants. However, prototype phosphodiesterase 4 inhibitors show severe side effects, including nausea and vomiting. N-Isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel phosphodiesterase 4 inhibitor with little emetic potential. In the present study, we investigated the inhibitory effect of FCPR03 on chronic unpredictable mild stress-induced, depressive-like behaviors in mice and explored the underlying mechanisms. Methods: The depression model of mice was established by chronic unpredictable mild stress. Forced swim test, tail suspension test, and sucrose preference test were used to assess depressive-like behaviors. Golgi-staining was utilized to analyze dendritic morphology and spine density. The level of cAMP was measured by enzyme-linked immnosorbent assay assay. Western blot was used to evaluate protein levels of phosphorylated cAMP-response element binding protein, protein kinase B, glycogen synthase kinase-3ß, and brain derived neurotrophic factor in both hippocampus and prefrontal cortex. Postsynaptic density protein 95 and synapsin 1 were also detected by western blot in the hippocampi. Results: Treatment with FCPR03 (0.5-1.0 mg/kg, i.p.) increased consumption of sucrose in the sucrose preference test in mice exposed to chronic unpredictable mild stress. FCPR03 shortened the immobility time in forced swim test and tail suspension test without affecting locomotor activity. Furthermore, chronic unpredictable mild stress decreased the dendritic spine density and dendritic length in the hippocampus. This change was accompanied by decreased expression of postsynaptic density protein 95 and synapsin 1. Interestingly, FCPR03 prevented dendritic spine loss and increased synaptic protein levels. Moreover, the levels of cAMP, phosphorylated cAMP-response element binding protein, and brain derived neurotrophic factor were elevated in chronic unpredictable mild stress-challenged mice after treatment with FCPR03. In addition, FCPR03 also enhanced the phosphorylation of both protein kinase B and glycogen synthase kinase-3ß in mice exposed to chronic unpredictable mild stress. Conclusion: The present study suggests that FCPR03 could prevent both depressive-like behaviors and spine loss induced by chronic unpredictable mild stress in the mice hippocampi.


Subject(s)
Behavior, Animal/drug effects , Benzamides/pharmacology , Dendritic Spines/drug effects , Depression/drug therapy , Hippocampus/drug effects , Phosphodiesterase 4 Inhibitors/pharmacology , Stress, Psychological/complications , Animals , Dendritic Spines/pathology , Depression/etiology , Disease Models, Animal , Hippocampus/pathology , Male , Mice , Mice, Inbred C57BL
15.
Redox Biol ; 16: 47-58, 2018 06.
Article in English | MEDLINE | ID: mdl-29475134

ABSTRACT

Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5-50 µM) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25 µM) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (Δψm) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of Δψm in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Parkinson Disease/genetics , Phosphodiesterase 4 Inhibitors/pharmacology , Reactive Oxygen Species/metabolism , 1-Methyl-4-phenylpyridinium , Apoptosis/drug effects , Caspase 3/genetics , Cell Line , Cell Survival/drug effects , Cyclic AMP Response Element-Binding Protein/antagonists & inhibitors , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Humans , Isoquinolines/pharmacology , Membrane Potential, Mitochondrial/drug effects , Oxidative Stress/drug effects , Parkinson Disease/drug therapy , Parkinson Disease/pathology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/drug effects , Sulfonamides/pharmacology
16.
RSC Adv ; 8(69): 39384-39393, 2018 Nov 23.
Article in English | MEDLINE | ID: mdl-35558033

ABSTRACT

A new, convenient, and efficient precursor transformation route for the synthesis of supported Au nanocatalysts was reported. In this strategy, [Au(en)2]3+-riched titanate nanospheres (en: ethylenediamine) with hierarchical flower-like architecture were pre-synthesized via "ammonia etching-ion exchange" processes and then used as the precursors of the objective catalysts. Direct pyrolysis of these precursors, varying in amount of [Au(en)2]3+, led to the formation of Au nanoparticles (AuNPs) with different contents uniformly supported on highly crystalline titania nanoflowers (fTiO2). The fTiO2-supported AuNPs nanocomposites possessed highly open porous structures with large surface areas (142.3-149.3 m2 g-1), which could allow guest molecules to diffuse in and out easily. More interestingly, the formed AuNPs with small size (∼3.8 nm) were well-dispersed and partially embedded into the nanosheets of fTiO2, which was beneficial for achieving high activity while avoiding their detachment from the support during application. Accordingly, the AuNPs/TiO2 catalysts exhibited superior catalytic properties for 4-nitrophenol hydrogenation with significantly higher catalytic efficiencies than many previously reported heterogeneous catalysts. Moreover, the catalytic activity could remain almost unchanged after being recycled several times, demonstrating their high stability. These findings open up a new possibility for rational design and synthesis of supported catalysts for diverse catalytic applications.

17.
Orthop Surg ; 9(1): 69-76, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28371502

ABSTRACT

OBJECTIVE: To compare clinical and radiographic outcomes of posterior malleolar fractures (PMF) treated with lag screws from anterior to posterior versus posterior to anterior approach. METHODS: We retrospectively analyzed 48 patients with trimalleolar fractures who underwent open reduction and internal fixation (ORIF) with either posteromedial (PM) or posterolateral (PL) approaches between January 2012 and December 2014. Fixation of the posterior malleolus was made with anteroposterior screws in 20 patients using the PM approach and posteroanterior screws in 28 patients using the PL approach. The American Orthopedic Foot and Ankle Society (AOFAS) scores and range of motion (ROM) of the ankle were used as the main outcome measurements, and results were evaluated at the 6-month, 12-month and final follow-up. Postoperative radiographs and computed tomography scans were used to evaluate the residual gap/step-off. The degree of arthritis was evaluated on final follow-up using Bargon criteria. Other complications were also recorded to compare the clinical outcomes of the two approaches. RESULT: The mean duration of follow-up regardless of the approaches was 21.1 months (range, 15-54 months). None of the patients developed delayed union or nonunion. Functional bone healing was obtained in all patients at 10.7 weeks (range, 8-16 weeks). The mean AOFAS scores of the PM group at the postoperative 6-mouth, 12-month, and final follow-up were 91.4 (range, 82-100), 92.5 (range, 84-100), and 92.9 (range, 86-100), respectively. In the PL group, the mean AOFAS scores were 89.9 (range, 72-100), 91.4 (range, 77-100), and 91.9 (range, 77-100), respectively. At the final follow-up, the median loss of range of motion (ROM) for dorsiflexion and plantaflexion were 0°(0°, 5°) and 0°(0°, 0°), respectively, in both groups. There were no significant differences between the two approaches in AOFAS scores and ROM of the ankle in each period postoperatively (P > 0.05). Two patients in the PL group and 1 in the PM group developed Bargon grade 2 or 3 arthritis. We detected a 2-mm and 3-mm step-off in 1 patient in the PM and PL groups, respectively. CONCLUSION: Satisfactory results were obtained by using the two approaches for fixation of posterior malleolus, and the approaches have similar clinical and radiographic outcomes. Surgeons should choose the appropriate approach based on their experience.


Subject(s)
Ankle Fractures/surgery , Fracture Fixation, Internal/methods , Adolescent , Adult , Ankle Fractures/diagnostic imaging , Ankle Joint/diagnostic imaging , Ankle Joint/physiopathology , Ankle Joint/surgery , Bone Screws , Female , Follow-Up Studies , Fracture Fixation, Internal/adverse effects , Fracture Fixation, Internal/instrumentation , Fracture Healing , Humans , Male , Middle Aged , Postoperative Care/methods , Radiography , Range of Motion, Articular , Retrospective Studies , Surgical Wound Infection/etiology , Tomography, X-Ray Computed , Young Adult
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